ORCID Profile
0000-0002-8075-6275
Current Organisations
Olivia Newton-John Cancer Wellness & Research Centre
,
Technical University of Munich
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Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.YEXCR.2007.03.027
Abstract: Tumor necrosis factor (TNF) antagonists represent a milestone in the therapy of autoimmune conditions. Anti-TNF antibodies have been approved for clinical use and during the last eight years thousands of patients have been treated. However, the long-term sequelae of anti-TNF agents in promoting carcinogenesis remain unclear. This study sought to define the role of intra-tumor TNF-alpha production on cancer cell progression and to determine whether TNF-alpha antibodies can suppress anti-tumoral immunity. Using an experimental animal tumor model we demonstrate that anti-TNF-alpha antibodies hinder anti-tumor immune responses and promote growth of immunogenic rat colon tumors (REG) that are always rejected by immunocompetent untreated rats. The major role of TNF-alpha in the anti-tumoral immune response was confirmed by transfecting progressive and tolerogenic rat colon tumor cells (PRO) with the TNF-alpha gene. PRO tumor cells secreting TNF-alpha induce tumor-infiltrating dendritic cell (DC) activation. This triggers a potent immune response leading to tumor rejection and long-lasting immunity. Therefore, the prominent role of TNF-alpha in anti-tumoral immune responses underscores the need for caution and close surveillance following the administration of TNF inhibitors.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2014
Abstract: The pro-apoptotic BH3-only BCL-2 family member BIM is a critical determinant of hematopoietic cell development and homeostasis. It has been argued that the striking hematopoietic abnormalities of BIM-deficient mice (accumulation of lymphocytes and granulocytes) may be the result of the loss of the protein throughout the whole animal rather than a consequence intrinsic to the loss of BIM in hematopoietic cells. To address this issue and allow the deletion of BIM in specific cell types in future studies, we have developed a mouse strain with a conditional Bim allele as well as a new Cre transgenic strain, Vav-CreER , in which the tamoxifen-inducible CreER recombinase (fusion protein) is predominantly expressed in the hematopoietic system. We show that acute loss of BIM in the adult mouse rapidly results in the hematopoietic phenotypes previously observed in mice lacking BIM in all tissues. This includes changes in thymocyte subpopulations, increased white blood cell counts and resistance of lymphocytes to BIM-dependent apoptotic stimuli, such as cytokine deprivation. We have validated this novel conditional Bim knockout mouse model using established and newly developed CreER strains ( Rosa26-CreER and Vav-CreER ) and will make these exciting new tools for studies on cell death and cancer available.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2014
DOI: 10.1038/LEU.2014.1
Abstract: Overexpression of the prosurvival protein Bcl-2 marks many B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL, causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2-selective antagonist, ABT-199. Here we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B-cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the probable impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients, and have implications for monitoring during ABT-199 therapy as well as for the clinical utility of this very promising targeted agent.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.CCR.2013.06.002
Abstract: The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 18-08-2022
DOI: 10.1038/S41568-022-00500-2
Abstract: Tumours are often composed of a multitude of malignant clones that are genomically unique, and only a few of them may have the ability to escape cancer therapy and grow as symptomatic lesions. As a result, tumours with a large degree of genomic ersity have a higher chance of leading to patient death. However, clonal fate can be driven by non-genomic features. In this context, new technologies are emerging not only to track the spatiotemporal fate of in idual cells and their progeny but also to study their molecular features using various omics analysis. In particular, the recent development of cellular barcoding facilitates the labelling of tens to millions of cancer clones and enables the identification of the complex mechanisms associated with clonal fate in different microenvironments and in response to therapy. In this Review, we highlight the recent discoveries made using lentiviral-based cellular barcoding techniques, namely genetic and optical barcoding. We also emphasize the strengths and limitations of each of these technologies and discuss some of the key concepts that must be taken into consideration when one is designing barcoding experiments. Finally, we suggest new directions to further improve the use of these technologies in cancer research.
Publisher: MDPI AG
Date: 24-01-2022
Abstract: Geno- and phenotypic heterogeneity amongst cancer cell subpopulations are established drivers of treatment resistance and tumour recurrence. However, due to the technical difficulty associated with studying such intra-tumoural heterogeneity, this phenomenon is seldom interrogated in conventional cell culture models. Here, we employ a fluorescent lineage technique termed “optical barcoding” (OBC) to perform simultaneous longitudinal tracking of spatio-temporal fate in 64 patient-derived colorectal cancer subclones. To do so, patient-derived cancer cell lines and organoids were labelled with discrete combinations of reporter constructs, stably integrated into the genome and thus passed on from the founder cell to all its clonal descendants. This strategy enables the longitudinal monitoring of in idual cell lineages based upon their unique optical barcodes. By designing a novel panel of six fluorescent proteins, the maximum theoretical subpopulation resolution of 64 discriminable subpopulations was achieved, greatly improving throughput compared with previous studies. We demonstrate that all subpopulations can be purified from complex clonal mixtures via flow cytometry, permitting the downstream isolation and analysis of any lineages of interest. Moreover, we outline an optimized imaging protocol that can be used to image optical barcodes in real-time, allowing for clonal dynamics to be resolved in live cells. In contrast with the limited intra-tumour heterogeneity observed in conventional 2D cell lines, the OBC technique was successfully used to quantify dynamic clonal expansions and contractions in 3D patient-derived organoids, which were previously demonstrated to better recapitulate the heterogeneity of their parental tumour material. In summary, we present OBC as a user-friendly, inexpensive, and high-throughput technique for monitoring intra-tumoural heterogeneity in in vitro cell culture models.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2014
DOI: 10.1038/ONC.2014.313
Abstract: Evasion of cell death is fundamental to the development of cancer and its metastasis. The role of the BCL-2-mediated (intrinsic) apoptotic program in these processes remains poorly understood. Here we have investigated the relevance of the pro-apoptotic protein BIM to breast cancer progression using the MMTV-Polyoma middle-T (PyMT) transgenic model. BIM deficiency in PyMT females did not affect primary tumor growth, but substantially increased the survival of metastatic cells within the lung. These data reveal a role for BIM in the suppression of breast cancer metastasis. Intriguingly, we observed a striking correlation between the expression of BIM and the epithelial to mesenchymal transition transcription factor SNAI2 at the proliferative edge of the tumors. Overexpression and knockdown studies confirmed that these two genes were coordinately expressed, and chromatin immunoprecipitation analysis further revealed that Bim is a target of SNAI2. Taken together, our findings suggest that SNAI2-driven BIM-induced apoptosis may temper metastasis by governing the survival of disseminating breast tumor cells.
Publisher: Wiley
Date: 20-05-2008
DOI: 10.1038/ICB.2008.33
Publisher: Informa UK Limited
Date: 10-2007
Publisher: Portland Press Ltd.
Date: 09-01-2019
DOI: 10.1042/BST20180375
Abstract: Until recently, established cancer cell lines have been used extensively in breast cancer research, due largely to the difficulties associated with the manipulation and long-term maintenance in culture of primary tumour cells from patients. The recent development of organoid cultures has provided new opportunities to model and analyse patient s les, allowing the propagation of malignant cells under conditions that resemble the three-dimensional growth of breast tumours. They have proved efficacious in preserving the heterogeneity of primary s les and are emerging as a new model to further characterise the molecular features of breast cancer. Organoids formed from patient-derived cells are now in use for the evaluation of drug sensitivity and to validate disease-causing genomic variations. Here, the advantages and limitations of organoid cultures will be discussed and compared with the parallel development of other two- and three-dimensional culture strategies and with patient-derived xenografts. In particular, we will focus on the molecular characterisation of breast cancer organoids and provide some ex les of how they have been used in functional studies.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2018
DOI: 10.1038/S41388-018-0268-2
Abstract: Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells. Using patient-derived xenografts and specific inhibitors of BCL-2, BCL-XL, and MCL-1, we identified a greater reliance of lung SqCC cells on BCL-XL and MCL-1 compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitors alone provided a survival benefit in combination FGFR therapy in vivo. Only triple BCL-XL, MCL-1, and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC. Our work therefore provides a rationale for the inhibition of MCL-1, BCL-XL, and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.
Publisher: AIP Publishing
Date: 04-2020
DOI: 10.1063/5.0003886
Abstract: A small dimension Laval nozzle connected to a compact high enthalpy source equipped with cavity ringdown spectroscopy (CRDS) is used to produce vibrationally hot and rotationally cold high-resolution infrared spectra of polyatomic molecules in the 1.67 µm region. The Laval nozzle was machined in isostatic graphite, which is capable of withstanding high stagnation temperatures. It is characterized by a throat diameter of 2 mm and an exit diameter of 24 mm. It was designed to operate with argon heated up to 2000 K and to produce a quasi-unidirectional flow to reduce the Doppler effect responsible for line broadening. The hypersonic flow was characterized using computational fluid dynamics simulations, Pitot measurements, and CRDS. A Mach number evolving from 10 at the nozzle exit up to 18.3 before the occurrence of a first oblique shock wave was measured. Two different gases, carbon monoxide (CO) and methane (CH4), were used as test molecules. Vibrational (Tvib) and rotational (Trot) temperatures were extracted from the recorded infrared spectrum, leading to Tvib = 1346 ± 52 K and Trot = 12 ± 1 K for CO. A rotational temperature of 30 ± 3 K was measured for CH4, while two vibrational temperatures were necessary to reproduce the observed intensities. The population distribution between vibrational polyads was correctly described with TvibI=894±47 K, while the population distribution within a given polyad (namely, the dyad or the pentad) was modeled correctly by TvibII=54±4 K, testifying to a more rapid vibrational relaxation between the vibrational energy levels constituting a polyad.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2009
DOI: 10.1007/S10495-008-0308-4
Abstract: Members of the Bcl-2 family are essential regulators of programmed cell death and thus play a major role in the development and function of many tissues. The balance between pro-survival and pro-apoptotic members of the family decides whether a cell will live or die. This mechanism allows organisms to get rid of cells that are no longer needed or have become dangerous. Deregulation of apoptosis is a major contributing factor in the development of many diseases. A deeper understanding of how the Bcl-2 family proteins orchestrate death in normal and pathologic conditions is thus relevant not only for disease etiology, but also to try to prevent these various disorders. Experiments with transgenic and gene-ablated mice have helped elucidate the function of the different members of the Bcl-2 family and their physiological roles. The present review highlights the role of Bcl-2 family members in autoimmune and degenerative disorders, with a particular focus on the mouse models that have been used to study their function.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.CCELL.2018.11.004
Abstract: Defects in apoptotic cell death can promote cancer and impair responses of malignant cells to anti-cancer therapy. Pro-survival BCL-2 proteins prevent apoptosis by keeping the cell death effectors, BAX and BAK, in check. The BH3-only proteins initiate apoptosis by neutralizing the pro-survival BCL-2 proteins. Structural analysis and medicinal chemistry led to the development of small-molecule drugs that mimic the function of the BH3-only proteins to kill cancer cells. The BCL-2 inhibitor venetoclax has been approved for treatment of refractory chronic lymphocytic leukemia and this drug and inhibitors of pro-survival MCL-1 and BCL-XL are being tested in erse malignancies.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2010
DOI: 10.1038/CDD.2010.144
Publisher: Rockefeller University Press
Date: 06-06-2011
DOI: 10.1084/JEM.20100951
Abstract: For malignant growth, solid cancers must stimulate the formation of new blood vessels by producing vascular endothelial growth factor (VEGF-A), which is required for the survival of tumor-associated vessels. Novel anticancer agents that block VEGF-A signaling trigger endothelial cell (EC) apoptosis and vascular regression preferentially within tumors, but how the ECs die is not understood. In this study, we demonstrate that VEGF-A deprivation, provoked either by drug-induced tumor shrinkage or direct VEGF-A blockade, up-regulates the proapoptotic BH3 (Bcl-2 homology 3)-only Bcl-2 family member Bim in ECs. Importantly, the tumor growth inhibitory activity of a VEGF-A antagonist required Bim-induced apoptosis of ECs. These findings thus reveal the mechanism by which VEGF-A blockade induces EC apoptosis and impairs tumor growth. They also indicate that drugs mimicking BH3-only proteins may be exploited to kill tumor cells not only directly but also indirectly by ablating the tumor vasculature.
Publisher: Cambridge University Press
Date: 22-08-2011
Publisher: Rockefeller University Press
Date: 03-08-2009
Abstract: Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.
Publisher: American Society of Hematology
Date: 14-06-2012
DOI: 10.1182/BLOOD-2011-12-400929
Abstract: The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-xL, and Bcl-w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non-Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-xL predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-xL or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-xL/Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-07-2021
Abstract: Optical barcoding reveals enhanced TNFα activation and polyclonality in lung, but not liver, metastases from breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2019
DOI: 10.1038/S41467-019-09916-1
Abstract: The original version of this Article contained an error in Fig. 4. In the left histogram of the right panel of Fig. 4d, several data points were inadvertently deleted from the histogram during the production process. This error has been corrected in both the PDF and HTML versions of the Article. The original, incorrect version of Fig. 4 is presented in the accompanying Publisher Correction.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2004
Publisher: Springer Science and Business Media LLC
Date: 30-05-2006
DOI: 10.1007/S10495-006-8765-0
Abstract: The identification of the most efficient strategy for tumor antigen loading of dendritic cells (DCs) remains a challenge in cancer immunotherapy protocols. Autologous dead tumor cells have been demonstrated to constitute an acceptable source of multiple tumor-associated antigens (TAA) to pulse DCs. However the optimal approach for inducing cell death that would lead to effective endocytosis and activation of DCs remains controversial. In this study we have induced and defined 3 distinct mechanisms of tumor cell death (apoptosis, necrosis and fusion-mediated cell death), and investigated their differential effects on DCs. Bone marrow-derived DCs demonstrated comparable uptake of primary apoptotic, necrotic, or fused dead tumor cells. Furthermore, the distinct modes of cancer cell death had analogous potential in activating the transcription factors NF-kappaB and STAT1 and in maturing DCs, resulting in an equally effective stimulation of immune T cells. The current study therefore provides further informations on the use of dead whole tumor cells as antigen sources for effective active anti-cancer immunotherapy.
Publisher: MDPI AG
Date: 13-05-2022
Abstract: The development of therapies that target specific disease subtypes has dramatically improved outcomes for patients with breast cancer. However, survival gains have not been uniform across patients, even within a given molecular subtype. Large collections of publicly available drug screening data matched with transcriptomic measurements have facilitated the development of computational models that predict response to therapy. Here, we generated a series of predictive gene signatures to estimate the sensitivity of breast cancer s les to 90 drugs, comprising FDA-approved drugs or compounds in early development. To achieve this, we used a cell line-based drug screen with matched transcriptomic data to derive in silico models that we validated in large independent datasets obtained from cell lines and patient-derived xenograft (PDX) models. Robust computational signatures were obtained for 28 drugs and used to predict drug efficacy in a set of PDX models. We found that our signature for cisplatin can be used to identify tumors that are likely to respond to this drug, even in absence of the BRCA-1 mutation routinely used to select patients for platinum-based therapies. This clinically relevant observation was confirmed in multiple PDXs. Our study foreshadows an effective delivery approach for precision medicine.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 20-09-2005
Abstract: Arsenic trioxide (As(2)O(3)) is known to be toxic toward leukemia cells. In this study, we determined its effects on survival of human monocytic cells during macrophagic differentiation, an important biological process involved in the immune response. As(2)O(3) used at clinically relevant pharmacological concentrations induced marked apoptosis of human blood monocytes during differentiation with either granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor. Apoptosis of monocytes was associated with increased caspase activities and decreased DNA binding of p65 nuclear factor-kappaB (NF-kappaB) like As(2)O(3), the selective NF-kappaB inhibitor (E)-3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (Bay 11-7082) strongly reduced survival of differentiating monocytes. The role of NF-kappaB in arsenic toxicity was also studied in promonocytic U937 cells during phorbol 12-myristate 13-acetate-induced macrophagic differentiation. In these cells, As(2)O(3) first reduced DNA binding of p65 NF-kappaB and subsequently induced apoptosis. In addition, overexpression of the p65 NF-kappaB subunit, following stable infection with a p65 retroviral expressing vector, increased survival of As(2)O(3)-treated U937 cells. As(2)O(3) specifically decreased protein levels of X-linked inhibitor of apoptosis protein and FLICE-inhibitory protein, two NF-kappaB-regulated genes in both U937 cells and blood monocytes during their differentiations. Finally, As(2)O(3) was found to inhibit macrophagic differentiation of monocytic cells when used at cytotoxic concentrations however, overexpression of the p65 NF-kappaB subunit in U937 cells reduced its effects toward differentiation. In contrast to monocytes, well differentiated macrophages were resistant to low concentrations of As(2)O(3). Altogether, our study demonstrates that clinically relevant concentrations of As(2)O(3) induced marked apoptosis of monocytic cells during in vitro macrophagic differentiation likely through inhibition of NF-kappaB-related survival pathways.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
DOI: 10.1038/S41418-020-0541-0
Abstract: Smac mimetics target inhibitor of apoptosis (IAP) proteins, thereby suppressing their function to facilitate tumor cell death. Here we have evaluated the efficacy of the preclinical Smac-mimetic compound A and the clinical lead birinapant on breast cancer cells. Both exhibited potent in vitro activity in triple-negative breast cancer (TNBC) cells, including those from patient-derived xenograft (PDX) models. Birinapant was further studied using in vivo PDX models of TNBC and estrogen receptor-positive (ER + ) breast cancer. Birinapant exhibited single agent activity in all TNBC PDX models and augmented response to docetaxel, the latter through induction of TNF. Transcriptomic analysis of TCGA datasets revealed that genes encoding mediators of Smac-mimetic-induced cell death were expressed at higher levels in TNBC compared with ER + breast cancer, resulting in a molecular signature associated with responsiveness to Smac mimetics. In addition, the cell death complex was preferentially formed in TNBCs versus ER + cells in response to Smac mimetics. Taken together, our findings provide a rationale for prospectively selecting patients whose breast tumors contain a competent death receptor signaling pathway for the further evaluation of birinapant in the clinic.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2021
DOI: 10.1038/S41592-021-01203-6
Abstract: Understanding intratumoral heterogeneity-the molecular variation among cells within a tumor-promises to address outstanding questions in cancer biology and improve the diagnosis and treatment of specific cancer subtypes. Single-cell analyses, especially RNA sequencing and other genomics modalities, have been transformative in revealing novel biomarkers and molecular regulators associated with tumor growth, metastasis and drug resistance. However, these approaches fail to provide a complete picture of tumor biology, as information on cellular location within the tumor microenvironment is lost. New technologies leveraging multiplexed fluorescence, DNA, RNA and isotope labeling enable the detection of tens to thousands of cancer subclones or molecular biomarkers within their native spatial context. The expeditious growth in these techniques, along with methods for multiomics data integration, promises to yield a more comprehensive understanding of cell-to-cell variation within and between in idual tumors. Here we provide the current state and future perspectives on the spatial technologies expected to drive the next generation of research and diagnostic and therapeutic strategies for cancer.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2012
DOI: 10.1038/ONC.2011.508
Publisher: Springer Science and Business Media LLC
Date: 16-06-2008
DOI: 10.1038/ONC.2008.197
Abstract: A pair of isogenic colon carcinoma cells, SW480 and 620, was used to investigate the mechanisms of acquired tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance during tumour progression. Whereas primary tumour SW480 cells are sensitive to TRAIL-induced apoptosis, metastatic SW620 cells are resistant. The apoptotic signalling activated by TRAIL in SW480 cells is a type II pathway. We show that in SW620 cells, although caspase-8 is recruited and activated at the death-inducing-signalling complex and Bid is cleaved, this does not lead to caspase-9 activation. Comparison of Bcl-2, Bcl-xL and Mcl-1 levels in both cell lines showed no difference. In SW620 cells transfected with a tBid-GFP construct, tBid-GFP was correctly localized to the mitochondria. Thus, the resistance of SW620 cells is at the level of the mitochondria that can withstand large amounts of tBid. Although caspase-3 was directly cleaved by caspase-8 in SW620 cells to yield the p20 fragment, no further autocatalytic maturation into the p17 fragment was observed. We show that, in contrast to SW480 cells, the SW620 cell line expresses high amounts of X-linked inhibitor of apoptosis (XIAP). Downregulation of XIAP with bortezomib or small-interfering RNA was sufficient to restore the sensitivity of SW620 cells to TRAIL-induced apoptosis in the absence of SMAC/Diablo or cytochrome c release from the mitochondria. Thus, SW620 cells have developed a dual resistance to TRAIL-induced apoptosis: a block at the level of the mitochondria and, after a conversion to a type I pathway, an increased expression of XIAP which inhibits this pathway.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2019
DOI: 10.1038/S41467-019-08595-2
Abstract: Primary triple negative breast cancers (TNBC) are prone to dissemination but sub-clonal relationships between tumors and resulting metastases are poorly understood. Here we use cellular barcoding of two treatment-naïve TNBC patient-derived xenografts (PDXs) to track the spatio-temporal fate of thousands of barcoded clones in primary tumors, and their metastases. Tumor resection had a major impact on reducing clonal ersity in secondary sites, indicating that most disseminated tumor cells lacked the capacity to ‘seed’, hence originated from ‘shedders’ that did not persist. The few clones that continued to grow after resection i.e. ‘seeders’, did not correlate in frequency with their parental clones in primary tumors. Cisplatin treatment of one BRCA1 -mutated PDX model to non-palpable levels had a surprisingly minor impact on clonal ersity in the relapsed tumor yet purged 50% of distal clones. Therefore, clonal features of shedding, seeding and drug resistance are important factors to consider for the design of therapeutic strategies.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-08-2017
DOI: 10.1126/SCITRANSLMED.AAM7049
Abstract: The MCL-1 inhibitor S63845 is effective in combination with conventional therapy for targeting triple-negative and HER2- lified breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 02-09-2016
DOI: 10.1038/CDD.2016.82
Publisher: Research Square Platform LLC
Date: 25-07-2023
DOI: 10.21203/RS.3.RS-3112884/V1
Abstract: Metastatic BRAF V600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAF V600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAF V600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAF V600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-X L , and that combining encorafenib with a BCL-X L inhibitor significantly enhances apoptosis in BRAF V600E CRC cell lines. This effect was directly dependent on the induction of BIM as BIM deletion markedly attenuated BRAF plus BCL-X L inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-X L inhibition, we also examined the effect of combining encorafenib with the BCL-X L targeting PROTAC DT2216, and the novel BCL-2/BCL-X L inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased the induction of apoptosis in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAF V600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-X L inhibition significantly enhances apoptosis in pre-clinical models of BRAF V600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.
Publisher: Informa UK Limited
Date: 10-2006
DOI: 10.1128/MCB.00520-06
Publisher: Springer Science and Business Media LLC
Date: 07-08-2023
DOI: 10.1038/S42003-023-05167-5
Abstract: Intratumoural heterogeneity is associated with poor outcomes in breast cancer. To understand how malignant clones survive and grow in metastatic niches, in vivo models using cell lines and patient-derived xenografts (PDX) have become the gold standard. Injections of cancer cells in orthotopic sites (spontaneous metastasis assays) or into the vasculature (experimental metastasis assays) have been used interchangeably to study the metastatic cascade from early events or post-intravasation, respectively. However, less is known about how these different routes of injection impact heterogeneity. Herein we directly compared the clonality of spontaneous and experimental metastatic assays using the human cell line MDA-MB-231 and a PDX model. Genetic barcoding was used to study the fitness of the subclones in primary and metastatic sites. Using spontaneous assays, we found that intraductal injections resulted in less erse tumours compared to other routes of injections. Using experimental metastasis assays via tail vein injection of barcoded MDA-MB-231 cells, we also observed an asymmetry in metastatic heterogeneity between lung and liver that was not observed using spontaneous metastasis assays. These results demonstrate that these assays can result in ergent clonal outputs in terms of metastatic heterogeneity and provide a better understanding of the biases inherent to each technique.
Publisher: Public Library of Science (PLoS)
Date: 20-05-2011
Publisher: Springer Science and Business Media LLC
Date: 13-08-2019
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.BCP.2007.07.036
Abstract: Bleomycin (BLM) has demonstrated potent activity in treating malignant lymphomas but its therapeutic efficacy is h ered by induction of lung fibrosis. This side effect is related to the ability of the drug to generate reactive oxygen species in lung cells. In the present study, we evaluated the consequences of deglycosylation of BLM in term of cytotoxic activity and generation of reactive oxygen species. When tested on U937 human lymphoma cells, both compounds generated a typical apoptotic phenotype. Cell death induction was associated with Bax oligomerization, dissipation of the mitochondrial membrane potential, release of cytochrome c, caspase activation, chromatin condensation and internucleosomal degradation. Whereas both reactive oxygen species and c-jun NH(2)-terminal kinase (JNK) inhibitors prevented BLM-induced U937 cell death, only JNK inhibition prevented deglycosylated BLM-mediated cell death. Both compounds induced clustering of TRAIL receptors (DR4 and DR5) and Fas at the cell surface but neither a chimeric soluble DR5 receptor that inhibits TRAIL-induced cell death nor a dominant negative version of the adaptor molecule Fas-associated death domain prevented BLM-induced cytotoxicity. These observations indicate that deglycosylation of BLM does not impair the ability of the drug to trigger cell death through activation of the intrinsic pathway but prevents induction of reactive oxygen species. This observation suggests that deglycosylated BLM could exhibit less toxic side effects and could warrant its use in clinic.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2012
DOI: 10.1038/CDD.2011.198
Publisher: Wiley
Date: 22-06-2012
DOI: 10.1111/J.1365-2869.2012.01025.X
Abstract: Studies have repeatedly shown that electroencephalographic power during sleep is enhanced in the spindle frequency range following radio frequency electromagnetic field exposures pulse-modulated with fundamental frequency components of 2, 8, 14 or 217 Hz and combinations of these. However, signals used in previous studies also had significant harmonic components above 20 Hz. The current study aimed: (i) to determine if modulation components above 20 Hz, in combination with radio frequency, are necessary to alter the electroencephalogram and (ii) to test the demodulation hypothesis, if the same effects occur after magnetic field exposure with the same pulse sequence used in the pulse-modulated radio frequency exposure. In a randomized double-blind crossover design, 25 young healthy men were exposed at weekly intervals to three different conditions for 30 min before sleep. Cognitive tasks were also performed during exposure. The conditions were a 2-Hz pulse-modulated radio frequency field, a 2-Hz pulsed magnetic field, and sham. Radio frequency exposure increased electroencephalogram power in the spindle frequency range. Furthermore, delta and theta activity (non-rapid eye movement sleep), and alpha and delta activity (rapid eye movement sleep) were affected following both exposure conditions. No effect on sleep architecture and no clear impact of exposure on cognition was observed. These results demonstrate that both pulse-modulated radio frequency and pulsed magnetic fields affect brain physiology, and the presence of significant frequency components above 20 Hz are not fundamental for these effects to occur. Because responses were not identical for all exposures, the study does not support the hypothesis that effects of radio frequency exposure are based on demodulation of the signal only.
Publisher: American Association for Cancer Research (AACR)
Date: 2007
DOI: 10.1158/0008-5472.CAN-06-1610
Abstract: Tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent that induces apoptosis in cancer cells but not in most normal cells. How tumor physiology, particularly acidic extracellular pH (pHe), would modify sensitivity of cancer cells to TRAIL-induced cell death is not known. We have previously shown that cancer cells, resistant to TRAIL-induced apoptosis at physiologic pHe (7.4), could be sensitized to TRAIL at acidic pHe (6.5). However, at this acidic pHe, cell death was necrotic. We show here that, in spite of a necrosis-like cell death morphology, caspases are activated and are necessary for TRAIL-induced cell death at acidic pHe in HT29 human colon cancer cells. Furthermore, we observed that, whereas receptor-interacting protein (RIP) was cleaved following TRAIL treatment at physiologic pHe (7.4), it was not cleaved following TRAIL treatment at acidic pHe (6.5). Moreover, RIP degradation by geldanamycin or decrease expression of RIP by small RNA interference transfection inhibited TRAIL-induced necrosis at acidic pHe, showing that RIP was necessary for this necrotic cell death pathway. We also show that RIP kinase activity was essential for this cell death pathway. Altogether, we show that, under acidic pHe conditions, TRAIL induces a necrosis-like cell death pathway that depends both on caspases and RIP kinase activity. Thus, our data suggest for the first time that RIP-dependent necrosis might be a major death pathway in TRAIL-based therapy in solid tumors with acidic pHe. [Cancer Res 2007 (1):218–26]
Publisher: Springer Science and Business Media LLC
Date: 10-08-2015
DOI: 10.1038/ONC.2015.287
Abstract: The last three decades have seen significant progress in our understanding of the role of the pro-survival protein BCL-2 and its family members in apoptosis and cancer. BCL-2 and other pro-survival family members including Mcl-1 and BCL-XL have been shown to have a key role in keeping pro-apoptotic 'effector' proteins BAK and BAX in check. They also neutralize a group of 'sensor' proteins (such as BIM), which are triggered by cytotoxic stimuli such as chemotherapy. BCL-2 proteins therefore have a central role as guardians against apoptosis, helping cancer cells to evade cell death. More recently, an increasing number of BH3 mimetics, which bind and neutralize BCL-2 and/or its pro-survival relatives, have been developed. The utility of targeting BCL-2 in hematological malignancies has become evident in early-phase studies, with remarkable clinical responses seen in heavily pretreated patients. As BCL-2 is overexpressed in ~75% of breast cancer, there has been growing interest in determining whether this new class of drug could show similar promise in breast cancer. This review summarizes our current understanding of the role of BCL-2 and its family members in mammary gland development and breast cancer, recent progress in the development of new BH3 mimetics as well as their potential for targeting estrogen receptor-positive breast cancer.
Publisher: Wiley
Date: 09-2023
DOI: 10.1002/CTM2.1356
Location: Australia
Location: Australia
No related grants have been discovered for Delphine Merino.