ORCID Profile
0000-0002-7720-5077
Current Organisations
Virginia Tech
,
KU Leuven - University of Leuven
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Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618428
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641326
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: MDPI AG
Date: 27-03-2022
Abstract: Due to advances in the detection and management of prostate cancer over the past 20 years, most cases of localised disease are now potentially curable by surgery or radiotherapy, or amenable to active surveillance without treatment. However, this has given rise to a new dilemma for disease management the inability to distinguish indolent from lethal, aggressive forms of prostate cancer, leading to substantial overtreatment of some patients and delayed intervention for others. Driving this uncertainty is the critical deficit of novel targets for systemic therapy and of validated biomarkers that can inform treatment decision-making and to select and monitor therapy. In part, this lack of progress reflects the inherent challenge of undertaking target and biomarker discovery in clinical prostate tumours, which are cellularly heterogeneous and multifocal, necessitating the use of spatial analytical approaches. In this review, the principles of mass spectrometry-based lipid imaging and complementary gene-based spatial omics technologies, their application to prostate cancer and recent advancements in these technologies are considered. We put in perspective studies that describe spatially-resolved lipid maps and metabolic genes that are associated with prostate tumours compared to benign tissue and increased risk of disease progression, with the aim of evaluating the future implementation of spatial lipidomics and complementary transcriptomics for prognostication, target identification and treatment decision-making for prostate cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618425
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641323
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618422
Abstract: Table S9: CEBPA_UP signature
Publisher: Cold Spring Harbor Laboratory
Date: 28-08-2023
DOI: 10.1101/2023.08.28.555056
Abstract: Recent advances in spatial omics methods are revolutionising biomedical research by enabling detailed molecular analyses of cells and their interactions in their native state. As most technologies capture only a specific type of molecules, there is an unmet need to enable integration of multiple spatial-omics datasets. This, however, presents several challenges as these analyses typically operate on separate tissue sections at disparate spatial resolutions. Here, we established a spatial multi-omics integration pipeline enabling co-registration and granularity matching, and applied it to integrate spatial transcriptomics, mass spectrometry-based lipidomics, single nucleus RNA-seq and histomorphological information from human prostate cancer patient s les. This approach revealed unique correlations between lipids and gene expression profiles that are linked to distinct cell populations and histopathological disease states and uncovered molecularly different subregions not discernible by morphology alone. By its ability to correlate datasets that span across the biomolecular and spatial scale, the application of this novel spatial multi-omics integration pipeline provides unprecedented insight into the intricate interplay between different classes of molecules in a tissue context. In addition, it has unique hypothesis-generating potential, and holds promise for applications in molecular pathology, biomarker and target discovery and other tissue-based research fields.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641311.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641329
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641305.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618467.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579646.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641287
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641320
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579598.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641284
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641320.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: Springer Science and Business Media LLC
Date: 03-2002
DOI: 10.1007/S00223-001-2065-Z
Abstract: Testosterone (T) can affect bone metabolism not only directly, but also via its metabolites, estrogen or dihydrotestosterone, produced by enzymes present in bone. Therefore, the aim of this study was to investigate whether the high-affinity estrogen receptor ligand ICI 182,780 (ICI) impaired the bone-protective action of T in 3-month-old orchidectomized (Orch) rats, studied during an experimental period of 3 months. As expected, Orch significantly decreased trabecular bone volume in the proximal tibial metaphysis (-52%), as measured by histomorphometry, and had a similar negative effect on volumetric bone mineral density (BMD) in the distal femoral metaphysis (-53%), as assessed by peripheral quantitative computed tomography (pQCT). The loss of bone induced by Orch was completely prevented by T administration. Moreover, the Orch-associated increases of biochemical markers of bone turnover (serum osteocalcin, urinary deoxypyridinoline, and calcium excretion) did not occur when Orch rats received T. Administration of ICI in combination with T did not impair this bone-sparing effect. Cortical bone parameters (as determined by pQCT), body weight gain, and body composition (as measured by dual-energy X-ray absorptiometry) were not affected by T or ICI in combination with T. Furthermore, no differences were observed in serum concentrations of insulin-like growth factor-I or glucose homeostasis. In conclusion, ICI does not impair the long-term bone-protective effects of T in orchidectomized male rats, suggesting that testosterone can mediate its effect on the male skeleton directly via the androgen receptor. The absence of effects on body growth via the growth hormone--insulin-like growth factor-I axis may be a possible explanation for the lack of skeletal effects of this selective estrogen receptor antagonist.
Publisher: American Association for Cancer Research (AACR)
Date: 08-06-2022
DOI: 10.1158/1541-7786.MCR-21-1069
Abstract: Cancer cells feature increased macromolecular biosynthesis to support the formation of new organelles and membranes for cell ision. In particular, lipids are key macromolecules that comprise cellular membrane components, substrates for energy generation and mediators of inter- and intracellular signaling. The emergence of more sensitive and accurate technology for profiling the “lipidome” of cancer cells has led to unprecedented leaps in understanding the complexity of cancer metabolism, but also highlighted promising therapeutic vulnerabilities. Notably, fatty acids, as lipid building blocks, are critical players in all stages of cancer development and progression and the importance of fatty acid desaturation and its impact on cancer cell biology has been well established. Recent years have seen the reports of new mechanistic insights into the role of monounsaturated fatty acids (MUFA) in cancer, as regulators of cell death and lipid-related cellular signaling. This commentary aims to highlight these erse roles of MUFAs in cancer cells which may yield new directions for therapeutic interventions involving these important fatty acids.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579643
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.C.6713553.V3
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-7-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1501 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428964.V1
Abstract: Results of lipid association analyses
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641317
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641314.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641314
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.C.6713553.V1
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. /
Publisher: American Association for Cancer Research (AACR)
Date: 05-02-2021
DOI: 10.1158/0008-5472.CAN-20-2511
Abstract: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579640
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.C.6713553.V2
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618437
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618434
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641311
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428970.V1
Abstract: Supplementary Figures S1-S6
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618431
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579637.V1
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618464.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579643.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641308.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6513199.V1
Abstract: Abstract Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the “lipidome” in prostate tumors with matched benign tissues ( i n /i = 21), independent unmatched tissues ( i n /i = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide ( i n /i = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign s les. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched s les, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. Significance: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6513210.V1
Abstract: Abstract The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry–based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and i in vivo /i tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. Significance: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis. /
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579649
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579646
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428967.V1
Abstract: Patient and s le clinical characteristics
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618449
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579625.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579631.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618446
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641317.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618443
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618440
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618470.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579640.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641332.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641326.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579628.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641338
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 06-08-2021
DOI: 10.1158/0008-5472.CAN-20-3863
Abstract: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618458
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641299
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641332
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579634.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618455
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618431.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618452
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428970
Abstract: Supplementary Figures S1-S6
Publisher: Wiley
Date: 09-2004
DOI: 10.1359/JBMR.040505
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641290
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641323.V1
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618428.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641296
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: Royal Society of Chemistry (RSC)
Date: 15-05-2013
DOI: 10.1039/C3LC50382H
Abstract: Thermal loading effects in flow-through electroporation microfluidic devices have been systematically investigated by using dye-based ratiometric luminescence thermometry. Fluorescence measurements have revealed the crucial role played by both the applied electric field and flow rate on the induced temperature increments at the electroporation sections of the devices. It has been found that Joule heating could raise the intra-channel temperature up to cytotoxic levels (>45 °C) only when conditions of low flow rates and high applied voltages are applied. Nevertheless, when flow rates and electric fields are set to those used in real electroporation experiments we have found that local heating is not larger than a few degrees, i.e. temperature is kept within the safe range (<32 °C). We also provide thermal images of electroporation devices from which the heat affected area can be elucidated. Experimental data have been found to be in excellent agreement with numerical simulations that have also revealed the presence of a non-homogeneous temperature distribution along the electroporation channel whose magnitude is critically dependent on both applied electric field and flow rate. Results included in this work will allow for full control over the electroporation conditions in flow-through microfluidic devices.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579604.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579610
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.C.6713553
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-7-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1501 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641338.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428967
Abstract: Patient and s le clinical characteristics
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618467
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22428964
Abstract: Results of lipid association analyses
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618464
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618461
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641296.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618434.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618437.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579613.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579616
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: Cold Spring Harbor Laboratory
Date: 06-12-2019
DOI: 10.1101/865626
Abstract: Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, which encodes the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown in PCa cells selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation in vivo . Mechanistically, targeting of DECR1 caused cellular accumulation of linoleic acid, enhanced mitochondrial oxidative stress and lipid peroxidation, and ferroptosis. These findings implicate PUFA oxidation via DECR1 as a previously unexplored facet of FAO that promotes survival of PCa cells.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618440.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579613
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2017
DOI: 10.1038/NMETH.4185
Abstract: We argue that the field of extracellular vesicle (EV) biology needs more transparent reporting to facilitate interpretation and replication of experiments. To achieve this, we describe EV-TRACK, a crowdsourcing knowledgebase (evtrack.org) that centralizes EV biology and methodology with the goal of stimulating authors, reviewers, editors and funders to put experimental guidelines into practice.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618425.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618446.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: Wiley
Date: 04-12-2021
Abstract: Matrix‐assisted laser/desorption ionisation‐mass spectrometry imaging (MALDI‐MSI) enables label‐free imaging of biomolecules in biological tissues. However, many molecules remain undetected due to their poor ionisation efficiencies. These poor ionisation efficiencies practically limit spatial resolution. Herein, we address this challenge for aromatic antioxidants by reporting an innovative approach involving sequential matrix‐assisted laser desorption and two‐photon ionisation of desorbed neutrals. It is shown that ion yields increase with reduced s ling areas obtained using sub‐threshold primarily laser fluence. This counterintuitive observation could arise from a reduction in radical/ion neutralisation reactions within the sparse plume and/or favorable molecular desorption under low fluence conditions. The utility of this approach is demonstrated for imaging tocopherols and ubiquinols in mouse brain and prostate cancer tissue. This can pave the way for improved sensitivity in MSI experiments at cellular and sub‐cellular resolutions.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22429005
Abstract: Supplementary figures 1-9 and legends.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579622.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641299.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579601.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618470
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579616.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: Springer Science and Business Media LLC
Date: 02-02-2023
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.CD-22-0411
Abstract: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641329.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579607
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618443.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579604
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579601
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618422.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641305
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579631
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618449.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579598
Abstract: Table S9: CEBPA_UP signature
Publisher: Wiley
Date: 12-04-2009
DOI: 10.1111/J.1365-2605.2009.00964.X
Abstract: Evidence from several models of hormone depletion and/or replacement and from knockout animals points to a key role of androgens in the control of spermatogenesis. In testes of mice with a Sertoli cell-selective ablation of the androgen receptor (SCARKO), transcriptional profiling, using microarray technology, revealed that, already on postnatal day 10,692 genes are differentially expressed compared with testes of control mice. Further evaluation of a subset of these genes by quantitative RT-PCR suggested that differences in expression may already be evident on day 8 or earlier. As the androgen receptor in mouse Sertoli cells becomes immunologically detectable around day 5, we tried to identify the earliest responses to androgens by a new transcriptional profiling study on testes from 6-day-old SCARKO and control mice. No obvious and novel early androgen response genes, potentially acting as mediators of subsequent indirect androgen actions, could be identified. However, several genes differentially expressed on day 10 already displayed a response to androgen receptor ablation on day 6. Quantitative RT-PCR studies for 12 of these genes on 10 paired SCARKO and control testes from 4-, 6-, 8-, 10-, 20- and 50-day-old mice revealed significant differences in expression level from day 4 onwards for three genes (Eppin, PCI, Cldn11) and from day 6 onwards for one more gene (Rhox5). For at least two of these genes (Rhox5 and Eppin), there is evidence for direct regulation via the androgen receptor. For three additional genes (Gpd1, Tubb3 and Tpd52l1) significantly lower expression in the SCARKO was noted from day 8 onwards. For all the studied genes, an impressive increase in transcript levels was observed between day 4-50 and differential expression was maintained in adulthood. It is concluded that the SCARKO model indicates incipient androgen action in mouse Sertoli cells from day 4 onwards.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641302
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618455.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-0001
DOI: 10.1158/2159-8290.23641308
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618461.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22429005.V1
Abstract: Supplementary figures 1-9 and legends.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618458.V1
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579637
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641284.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579634
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579649.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579607.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618452.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641290.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641302.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579628
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641287.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579610.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579625
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579622
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Location: United States of America
No related grants have been discovered for Johannes Swinnen.