ORCID Profile
0000-0002-8460-4367
Current Organisation
Uppsala University
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433315.V1
Abstract: Results of differential gene expression analysis between GTML tumours and GTS tumours.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526532.V1
Abstract: S2. Math1CrePtchlox/Ptchlox Math1 GFP mice display GFP expression in the majority of tumour cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433309.V1
Abstract: Results of differential gene expression analysis between pre-GTS1 tumor cells treated for 48 hours with DMSO or Dox.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433336.V1
Abstract: Supplementary figure 4
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433318
Abstract: List of genes that are part of a quiescent cell signature and display regions of differentially opened chromatin.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526517.V1
Abstract: GFAPCre:Sox9lox/lox mice are not viable
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526523
Abstract: Sox9 immunostaining pattern in a variety of Shh-MB genetic mouse models
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433324.V1
Abstract: Supplementary figure 1
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433333
Abstract: Supplementary figure 3
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526523.V1
Abstract: Sox9 immunostaining pattern in a variety of Shh-MB genetic mouse models
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526517
Abstract: GFAPCre:Sox9lox/lox mice are not viable
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433330
Abstract: Supplementary figure 2
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526514
Abstract: Medulloblastoma and granule cell precursor Gli1 target genes
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433336
Abstract: Supplementary figure 4
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433315
Abstract: Results of differential gene expression analysis between GTML tumours and GTS tumours.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433318.V1
Abstract: List of genes that are part of a quiescent cell signature and display regions of differentially opened chromatin.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433312
Abstract: Results of differential gene expression analysis between GTML3 tumor cells treated for 48 hours with DMSO or Dox.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433345.V1
Abstract: Supplementary figure 5
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526529.V1
Abstract: S3. Sox9 expression quantification
Publisher: EMBO
Date: 13-09-2016
Abstract: SOX 9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX 9 protein stability are poorly understood. Here, we show that SOX 9 is a substrate of FBW 7, a tumor suppressor, and a SCF ( SKP 1/ CUL 1/F‐box)‐type ubiquitin ligase. FBW 7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX 9 that is phosphorylated by GSK 3 kinase and consequently degraded by SCF FBW 7α . Failure to degrade SOX 9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. FBW 7 is either mutated or downregulated in medulloblastoma, and in cases where FBW 7 mRNA levels are low, SOX 9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Transcriptional profiling of medulloblastoma cells expressing a degradation‐resistant SOX 9 mutant reveals activation of pro‐metastatic genes and genes linked to cisplatin resistance. Finally, we show that pharmacological inhibition of PI 3K/ AKT / mTOR pathway activity destabilizes SOX 9 in a GSK 3/ FBW 7‐dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433312.V1
Abstract: Results of differential gene expression analysis between GTML3 tumor cells treated for 48 hours with DMSO or Dox.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526535.V1
Abstract: S1. Sox 9 and Sox 2 immunoreactivity in the developing cerebellum
Publisher: American Association for Cancer Research (AACR)
Date: 30-07-2021
DOI: 10.1158/1541-7786.MCR-21-0117
Abstract: Despite preclinical data indicating SOX9 plays a key role in SHH-MB biology, our data argue against SOX9 as a viable therapeutic target.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526514.V1
Abstract: Medulloblastoma and granule cell precursor Gli1 target genes
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433333.V1
Abstract: Supplementary figure 3
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6514337.V1
Abstract: Abstract Relapse is the leading cause of death in patients with medulloblastoma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC lification. In paired primary-recurrent patient s les, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected i in vivo /i from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial–mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse. Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433306.V1
Abstract: Resource Table
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433306
Abstract: Resource Table
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6514337
Abstract: Abstract Relapse is the leading cause of death in patients with medulloblastoma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC lification. In paired primary-recurrent patient s les, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected i in vivo /i from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial–mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse. Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526535
Abstract: S1. Sox 9 and Sox 2 immunoreactivity in the developing cerebellum
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433309
Abstract: Results of differential gene expression analysis between pre-GTS1 tumor cells treated for 48 hours with DMSO or Dox.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526532
Abstract: S2. Math1CrePtchlox/Ptchlox Math1 GFP mice display GFP expression in the majority of tumour cells
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433321
Abstract: Supplementary Figure Legends
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.C.6545124.V1
Abstract: Abstract Medulloblastoma is the most common malignant pediatric brain tumor and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors (GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9 sup low /sup GCP-like tumor cells constitute the bulk of both infant (Math1Cre: i Ptch1 sup lox/lox /sup /i ) and adult ( i Ptch1 sup LacZ/+ /sup /i ) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct i SOX9 /i populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: i SOX9 /i sup + /sup i MATH1 /i sup + /sup (GCP), i SOX9 /i sup + /sup i GFAP /i sup + /sup (astrocytes) and i SOX9 /i sup + /sup i MATH1 /i sup + /sup i GFAP /i sup + /sup (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated i Sox9 /i using a Math1Cre model system. Surprisingly, targeted ablation of i Sox9 /i in GCPs (Math1Cre: i Sox9 sup lox/lox /sup /i ) revealed no overt phenotype and loss of i Sox9 /i in SHH-MB (Math1Cre: i Ptch1 sup lox/lox /sup Sox9 sup lox/lox /sup /i ) does not affect tumor formation. Implications: Despite preclinical data indicating SOX9 plays a key role in SHH-MB biology, our data argue against SOX9 as a viable therapeutic target. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433321.V1
Abstract: Supplementary Figure Legends
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526526
Abstract: S4. Single cell sequencing data analysis
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526526.V1
Abstract: S4. Single cell sequencing data analysis
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433345
Abstract: Supplementary figure 5
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22526529
Abstract: S3. Sox9 expression quantification
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433324
Abstract: Supplementary figure 1
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22433330.V1
Abstract: Supplementary figure 2
Publisher: Informa UK Limited
Date: 08-11-2016
Publisher: American Association for Cancer Research (AACR)
Date: 11-10-2022
DOI: 10.1158/0008-5472.CAN-22-2108
Abstract: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
Location: United States of America
No related grants have been discovered for Fredrik Swartling.