Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma
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ABSTRACT:
PROVIDER: PRJNA680708 | ENA |
REPOSITORIES: ENA
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Project description:Tumor recurrence is a slow biological process involving therapy resistance, immune escape and metastasis and is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. By studying paired primary-recurrent patient samples and patient-derived xenografts we identified significant accumulation of SOX9-positive cells in relapses and metastases. They exist as rare, quiescent cells in Group 3 and Group 4 patients that constitute two thirds of medulloblastoma. To follow relapse at the single cell level we developed an inducible dual Tet Off animal model of MYC-driven MB, where MYC can be directed from treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells. SOX9 promoted immune escape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we further showed how doxorubicin and MGMT inhibitors are specifically targeting relapsing cells.
2022-10-28 | GSE162080 | GEO
Project description:SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here we show that SOX9 is a substrate of FBW7, a tumor suppressor and a SCF (Skp1-Cul1-F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase. Specifically, FBW7-alpha targets T236-phosphorylated SOX9 for ubiquitylation and proteasomal degradation. Further, we demonstrate that FBW7 inactivation stabilizes SOX9 protein promoting migration, metastasis and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. Notably, expression of mutationally stabilized SOX9-T236/240A in medulloblastoma cells coincides with activation of pro-metastatic genes. FBW7 is frequently downregulated in all medulloblastoma subgroups and mutated specifically in SHH-driven medulloblastoma. In cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Finally, pharmacological inhibition of PI3K/Akt/mTOR activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.
2016-09-13 | GSE84320 | GEO
Project description:Breast cancer mortality results from incurable recurrent tumors, putatively seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. We derived a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant chemotherapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identified the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for the linkage of glycosaminoglycans (GAGs) to proteins to generate proteoglycans and its germline loss-of-function causes skeletal dysplasias. We determined that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes, promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and suggest targeting of FGFR2 signaling as a novel approach to eradicate dormant RTCs, thereby preventing recurrence.
2024-01-01 | GSE241252 | GEO
Project description:Tumor therapy mainly targets the tumor bulk, but tends to fail to eradicate the small resistant population of dormant cancer cells (DCCs) that enable relapse and/or metastasis beyond therapy. Using chemoradiotherapy resistant assay and SETD4 expression of a histone lysine methyltransferase, DCCs with high capacity of tumor-initiation and tumorsphere formation were isolated from three types of breast tumors. Exogenous DEK, a nuclear protein, activated the DCCs by binding to open chromatin which decreased SETD4, up-regulated the MYC and down-regulated the P53 signaling pathways. DEK-containing exosomes in blood highly correlate with tumor progress and exosomal DEK promotes tumor relapse and metastasis beyond chemoradiotherapy. Beyond activation, these formerly dormant cancer cells lost their chemoradiotherapy resistance. In treatment of DEK-containing exosomes plus chemoradiotherapy in mice, three types of breast tumors were eliminated without recurrence. Prior DCCs reactivation, as triggered by exogenous DEK may provide treatment options that eliminate both metastasis and recurrence potential.
2024-01-07 | GSE164427 | GEO
Project description:Tumor therapy mainly targets the tumor bulk, but tends to fail to eradicate the small resistant population of dormant cancer cells (DCCs) that enable relapse and/or metastasis beyond therapy. Using chemoradiotherapy resistant assay and SETD4 expression of a histone lysine methyltransferase, DCCs with high capacity of tumor-initiation and tumorsphere formation were isolated from three types of breast tumors. Exogenous DEK, a nuclear protein, activated the DCCs by binding to open chromatin which decreased SETD4, up-regulated the MYC and down-regulated the P53 signaling pathways. DEK-containing exosomes in blood highly correlate with tumor progress and exosomal DEK promotes tumor relapse and metastasis beyond chemoradiotherapy. Beyond activation, these formerly dormant cancer cells lost their chemoradiotherapy resistance. In treatment of DEK-containing exosomes plus chemoradiotherapy in mice, three types of breast tumors were eliminated without recurrence. Prior DCCs reactivation, as triggered by exogenous DEK may provide treatment options that eliminate both metastasis and recurrence potential.
2024-01-07 | GSE164428 | GEO
Project description:Tumor therapy mainly targets the tumor bulk, but tends to fail to eradicate the small resistant population of dormant cancer cells (DCCs) that enable relapse and/or metastasis beyond therapy. Using chemoradiotherapy resistant assay and SETD4 expression of a histone lysine methyltransferase, DCCs with high capacity of tumor-initiation and tumorsphere formation were isolated from three types of breast tumors. Exogenous DEK, a nuclear protein, activated the DCCs by binding to open chromatin which decreased SETD4, up-regulated the MYC and down-regulated the P53 signaling pathways. DEK-containing exosomes in blood highly correlate with tumor progress and exosomal DEK promotes tumor relapse and metastasis beyond chemoradiotherapy. Beyond activation, these formerly dormant cancer cells lost their chemoradiotherapy resistance. In treatment of DEK-containing exosomes plus chemoradiotherapy in mice, three types of breast tumors were eliminated without recurrence. Prior DCCs reactivation, as triggered by exogenous DEK may provide treatment options that eliminate both metastasis and recurrence potential.
2024-01-07 | GSE164426 | GEO
Project description:Cellular dormancy and heterogeneous cell cycle lengths provide important explanations for treatment failure following adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC) yet the molecular control of the dormant versus cycling state remains unknown. In CRCs dormant cells are found to be highly clonogenic and resistant to chemotherapies. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumour cells.
2018-05-21 | GSE114012 | GEO
Project description:The transcription factor gene Sox9 plays various roles in development, including differentiation of the skeleton, testes, glia, and heart. Other functions of Sox9 remain enigmatic. Because Sox9 protein regulates expression of target genes, the identification of Sox9 targets should facilitate an understanding of the mechanisms of Sox9 action. To help identify Sox9 targets, we used microarray expression profiling to compare wild-type embryos to mutant embryos lacking activity for sox9a and sox9b, the zebrafish co-orthologs of Sox9. Candidate genes were further evaluated by whole mount in situ hybridization in wild-type and sox9 mutant embryos. Results identified genes expressed in cartilage (col2a1a and col11a2), retina (calb2a, calb2b, crx, neurod, rs1, sox4a and vsx1) and pectoral fin bud (klf2b and EST AI722369) as candidate targets for Sox9. Cartilage is a well-characterized Sox9 target, which validates this strategy, whereas retina represents a novel Sox9 function. Analysis of mutant phenotypes confirmed that Sox9 helps regulate the number of Müller glia and photoreceptor cells and helps organize the neural retina. These roles in eye development were previously unrecognized and reinforce the multiple functions that Sox9 plays in vertebrate development. In each experiment, RNA was isolated from 48h wildtype and sox9a, sox9b double mutant embryos and the gene expression profiles were compared using microarrays. Three biological replicate experiments were performed, and each biological replicate contained a dyeswap.
2010-05-16 | E-GEOD-13482 | biostudies-arrayexpress
Project description:The main cause of death in medulloblastoma is recurrence associated with leptomeningeal dissemination. Although the molecular basis of medulloblastoma has received considerable attention over the past decade, the role of microRNAs (miRNAs) in the acquisition of metastatic phenotype remains poorly understood. This study aimed to identify miRNA involved in leptomeningeal dissemination and to elucidate its target mechanisms. We analyzed miRNA expression profiles of 29 medulloblastomas according to the presence of cerebrospinal fluid (CSF) seeding. The differential expressed miRNAs (DEmiRNAs) were validated on 29 medulloblastoma tissues and three medulloblastoma cells. The biological function of the selected miRNA was evaluated using in vitro studies. A total of 12 DEmiRNAs were identified including miRNA-192 in medulloblastoma with seeding. The reduced expression of miRNA-192 was confirmed in tumor seeding group and the medulloblastoma cells. Overexpression of miRNA-192 inhibited cellular proliferation targeting dihydrofolate reductase (DHFR). MiRNA-192 decreased cellular anchoring via repression of integrin subunits (αV, β1, and β3) and CD47. Medulloblastoma with seeding showed specific DEmiRNAs compared with those without seeding. MicroRNA-192 suppresses leptomeningeal dissemination of medulloblastoma through modulating cell proliferation and anchoring ability. leptomeningeal dissemination in 29 pediatric medulloblastoma patients
2015-12-31 | E-GEOD-66968 | biostudies-arrayexpress
Project description:The transcription factor gene Sox9 plays various roles in development, including differentiation of the skeleton, testes, glia, and heart. Other functions of Sox9 remain enigmatic. Because Sox9 protein regulates expression of target genes, the identification of Sox9 targets should facilitate an understanding of the mechanisms of Sox9 action. To help identify Sox9 targets, we used microarray expression profiling to compare wild-type embryos to mutant embryos lacking activity for sox9a and sox9b, the zebrafish co-orthologs of Sox9. Candidate genes were further evaluated by whole mount in situ hybridization in wild-type and sox9 mutant embryos. Results identified genes expressed in cartilage (col2a1a and col11a2), retina (calb2a, calb2b, crx, neurod, rs1, sox4a and vsx1) and pectoral fin bud (klf2b and EST AI722369) as candidate targets for Sox9. Cartilage is a well-characterized Sox9 target, which validates this strategy, whereas retina represents a novel Sox9 function. Analysis of mutant phenotypes confirmed that Sox9 helps regulate the number of Müller glia and photoreceptor cells and helps organize the neural retina. These roles in eye development were previously unrecognized and reinforce the multiple functions that Sox9 plays in vertebrate development.
2008-11-08 | GSE13482 | GEO