Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA331047 | ENA |
REPOSITORIES: ENA
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Project description:Elucidating the pathogenesis of chemoresistance is fundamental for developing more effective interventions that will improve the clinical outcome of neoplastic diseases such as ovarian cancer. Here, we report the upregulation of PBX1, a stem cell reprogramming factor, in recurrent ovarian carcinomas. Moreover, high levels of PBX1 expression are correlated with a shorter survival rate among post-chemotherapy ovarian cancer patients. Ectopic expression of PBX1 promotes cancer stem cell-like phenotypes, including increased side population and ALDH activity, enhanced tumorigenicity at a low cell density, and increased resistance to platinum-based therapy. Silencing PBX1 in platinum-resistant cell lines that overexpress PBX1 sensitizes cells to platinum treatment and reduces their â??stemnessâ??. Analysis of previously reported genome-wide chromatin immunoprecipitation data shows that PBX1 binds directly to promoters of genes involved in stem cell maintenance and tissue injury response. We confirmed direct regulation of STAT3 by PBX1, and demonstrated that the PBX1 binding motif located on the STAT3 promoter participates in positive transcriptional regulation of STAT3. Furthermore, a STAT3/JAK2 inhibitor potently sensitizes platinum-resistant cells to carboplatin and suppresses their growth in vivo. These findings establish PBX1 as an upstream regulator of key pathways in stem cell and tissue damage response and highlight the potential of targeting the PBX1/STAT3 axis to overcome chemoresistance in human cancers. Determine gene expression changes after knockdown of PBX1 protein in an ovarian cancer cell line (OVCAR3)
2016-07-25 | E-GEOD-84755 | biostudies-arrayexpress
Project description:Elucidating the pathogenesis of chemoresistance is fundamental for developing more effective interventions that will improve the clinical outcome of neoplastic diseases such as ovarian cancer. Here, we report the upregulation of PBX1, a stem cell reprogramming factor, in recurrent ovarian carcinomas. Moreover, high levels of PBX1 expression are correlated with a shorter survival rate among post-chemotherapy ovarian cancer patients. Ectopic expression of PBX1 promotes cancer stem cell-like phenotypes, including increased side population and ALDH activity, enhanced tumorigenicity at a low cell density, and increased resistance to platinum-based therapy. Silencing PBX1 in platinum-resistant cell lines that overexpress PBX1 sensitizes cells to platinum treatment and reduces their “stemness”. Analysis of previously reported genome-wide chromatin immunoprecipitation data shows that PBX1 binds directly to promoters of genes involved in stem cell maintenance and tissue injury response. We confirmed direct regulation of STAT3 by PBX1, and demonstrated that the PBX1 binding motif located on the STAT3 promoter participates in positive transcriptional regulation of STAT3. Furthermore, a STAT3/JAK2 inhibitor potently sensitizes platinum-resistant cells to carboplatin and suppresses their growth in vivo. These findings establish PBX1 as an upstream regulator of key pathways in stem cell and tissue damage response and highlight the potential of targeting the PBX1/STAT3 axis to overcome chemoresistance in human cancers.
2016-07-25 | GSE84755 | GEO
Project description:Resistance to platinum-based chemotherapies remains a formidable challenge to the treatment of high-grade serous ovarian cancer (HGSOC). The complex and multifaceted nature of this cell state has been thought to originate in a small subpopulation of inherently resistant cancer stem cells (CSCs) in naïve tumors. However, there is increasing evidence that the chemoresistance state can be transiently acquired by non-stem cancer cells as well. Regardless of the route to chemoresistance, the key regulators of this process are poorly understood. Here, we use patient-derived single-cell RNA-Seq, multimodal sequencing, tumor microarray staining, and endogenous epigenetic modulation to show that SOX9 is a key driver of chemoresistance in HGSOC. We show that genetic or epigenetic upregulation of SOX9 is sufficient to induce chemoresistance in multiple ovarian cancer cell lines. Moreover, this upregulation induces the formation of a stem-like subpopulation and can significantly decrease tumor chemosensitivity in vivo. Mechanistically, SOX9 expression drives global transcriptional divergence and reprograms the transcriptional program of naïve cells into a stem-like state. Supporting this, our multi-omic single-cell analysis identified a rare cluster of SOX9-expressing cells that are highly enriched for CSCs and chemoresistance-associated stress gene modules in a naïve tumor. Notably, single cell profiles of naïve cells show that chemo treatment results in rapid population-level expression of SOX9 that enriches for a stem-like transcriptional state. Altogether, these findings implicate SOX9 as a critical regulator of early steps of transcriptional reprogramming that leads to chemoresistance through a cancer stem-like state in HGSOC.
2025-05-16 | GSE296599 | GEO
Project description:Resistance to platinum-based chemotherapies remains a formidable challenge to the treatment of high-grade serous ovarian cancer (HGSOC). The complex and multifaceted nature of this cell state has been thought to originate in a small subpopulation of inherently resistant cancer stem cells (CSCs) in naïve tumors. However, there is increasing evidence that the chemoresistance state can be transiently acquired by non-stem cancer cells as well. Regardless of the route to chemoresistance, the key regulators of this process are poorly understood. Here, we use patient-derived single-cell RNA-Seq, multimodal sequencing, tumor microarray staining, and endogenous epigenetic modulation to show that SOX9 is a key driver of chemoresistance in HGSOC. We show that genetic or epigenetic upregulation of SOX9 is sufficient to induce chemoresistance in multiple ovarian cancer cell lines. Moreover, this upregulation induces the formation of a stem-like subpopulation and can significantly decrease tumor chemosensitivity in vivo. Mechanistically, SOX9 expression drives global transcriptional divergence and reprograms the transcriptional program of naïve cells into a stem-like state. Supporting this, our multi-omic single-cell analysis identified a rare cluster of SOX9-expressing cells that are highly enriched for CSCs and chemoresistance-associated stress gene modules in a naïve tumor. Notably, single cell profiles of naïve cells show that chemo treatment results in rapid population-level expression of SOX9 that enriches for a stem-like transcriptional state. Altogether, these findings implicate SOX9 as a critical regulator of early steps of transcriptional reprogramming that leads to chemoresistance through a cancer stem-like state in HGSOC.
2025-05-16 | GSE297350 | GEO
Project description:Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the US. Ovarian cancer stem cells (OCSCs) have been shown to drive chemoresistance and tumor progression but the mechanism remains incompletely understood. Aldehyde Dehydrogenase 1A1 (ALDH1A1) is a robust marker for cancer stem cells in ovarian and other cancers. We demonstrate that ALDH1A1 inhibition suppresses stemness, chemoresistance and senescence in ovarian cancer.
2022-08-03 | GSE200641 | GEO
Project description:Widespread intraperitoneal metastases and chemoresistance render ovarian cancer the leading cause of gynecological malignancy–related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. The activation mechanism and key protumorigeneic events downstream of TGF-β signaling remain incompletely understood. Here, we identify hypoxic tumor microenvironment as an initiator of TGF-β signaling to promote HIF-2α positive CSC-mediated chemoresistance in high-grade serous ovarian cancer (HGSOC). Mechanistically, deubiquitinase USP9X, as a TGF-β downstream effector, stabilizes HIF-2ɑ in a hydroxylation- and ubiquitylation-dependent manner, thus promoting stemness reprogramming. Hypoxia and TGF-β signals converge on USP9X-HIF-2ɑ axis via multi-level regulations, which in turn facilitates Smad/HIF responses. Clinically, USP9X expression correlates with TGF-β signatures, CSCs characteristics, EMT behaviors, and chemotherapy responsiveness, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increasing chemosensitivity in orthotopic tumors, patient derived xenograft (PDX), organoid, and chemoresistant cell models, in part via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in stimulating TGF-β signaling, and a downstream USP9X-HIF-2ɑ proteostatic regulatory axis in priming the HGSOC stemness, thereby provides novel targeting venues to counteract TGF-β signaling in CSCs and meliorate clinical chemoresistance.
2025-04-05 | GSE286397 | GEO
Project description:Ovarian cancer (OC) displays the highest mortality among gynecological tumors, mainly due to early peritoneal dissemination, the high frequency of tumor relapse following primary debulking and the development of chemoresistance. All these events are thought to be initiated and sustained by a subpopulation of neoplastic cells, termed ovarian cancer stem cells (OCSC), that are endowed with self-renewing and tumor-initiating properties. This implies that interfering with OCSC function should offer novel therapeutic perspectives to defeat OC progression. To this aim, a better understanding of the molecular and functional makeup of OCSC in clinically relevant model systems is essential. We have profiled the transcriptome of OCSC vs. their bulk cell counterpart from a panel of patient-derived OC cell cultures. This revealed that Matrix Gla Protein (MGP), classically known as a calcification-preventing factor in cartilage and blood vessels, is markedly enriched in OCSC. Functional assays showed that MGP confers several stemness-associated traits to OC cells, including a transcriptional reprogramming. Patient-derived organotypic cultures pointed to the peritoneal microenvironment as a major inducer of MGP expression in OC cells. Furthermore, MGP was found to be necessary and sufficient for tumor initiation in OC mouse models, by shortening tumor latency and increasing dramatically the frequency of tumor-initiating cells. Mechanistically, MGP-driven OC stemness was mediated by the stimulation of Hedgehog signaling, in particular through the induction of the Hedgehog effector GLI1, thus highlighting a novel MGP/Hedgehog pathway axis in OCSC. Finally, MGP expression was found to correlate with poor prognosis in OC patients, and was increased in tumor tissue after chemotherapy, supporting the clinical relevance of our findings. Thus, MGP is a novel driver in OCSC pathophysiology, with a major role in stemness and in tumor initiation.
2023-05-10 | PXD037543 | Pride
Project description:We profile expression in serous epithelial ovarian carcinomas to assess the possibility of an miRNA signature associated with chemoresistance. Resistance to the available therapies is one of the main causes of low survival of patients with advanced epithelial ovarian cancer, thus representing an emergency in oncology. Here, we profiled miRNA expression in 86 naïve serous epithelial ovarian carcinomas (EOCs) to assess the possibility of miRNAs associated with chemoresistance. We identified 23 miRNAs associated with chemoresistance, of which three (miR-484, miR-642 and miR-217) were confirmed in the validation set (112 independent patients). The study of miR-484 role demonstrated that it regulated the chemoresistance of EOC cells acting not on cancer cells but on tumor vasculature. In particular, miR-484 is produced and secreted by chemosensitive EOC, therefore regulating the production of VEGFB by cancer cells and the expression of VEGFR2 in endothelial cells. Overall, we demonstrated that a three-miR signature can classify the response to chemotherapy and that chemoresistance in EOC relays, at least in part, on the control of tumor angiogenesis, indicating new options in the treatment of these patients. We analyzed tumor samples (<5% of normal tissue) from FFPE blocks of 86 patients with serous ovarian carcinomas.
2013-05-17 | E-GEOD-43867 | biostudies-arrayexpress
Project description:<h4>Background</h4>Cancer metabolism is emerging as an important focus area in cancer research. However, the in vitro cell culture conditions under which much cellular metabolism research is performed differ drastically from in vivo tumor conditions, which are characterized by variations in the levels of oxygen, nutrients like glucose, and other molecules like chemotherapeutics. Moreover, it is important to know how the diverse cell types in a tumor, including cancer stem cells that are believed to be a major cause of cancer recurrence, respond to these variations. Here, in vitro environmental perturbations designed to mimic different aspects of the in vivo environment were used to characterize how an ovarian cancer cell line and its derived, isogenic cancer stem cells metabolically respond to environmental cues.<h4>Results</h4>Mass spectrometry was used to profile metabolite levels in response to in vitro environmental perturbations. Docetaxel, the chemotherapeutic used for this experiment, caused significant metabolic changes in amino acid and carbohydrate metabolism in ovarian cancer cells, but had virtually no metabolic effect on isogenic ovarian cancer stem cells. Glucose deprivation, hypoxia, and the combination thereof altered ovarian cancer cell and cancer stem cell metabolism to varying extents for the two cell types. Hypoxia had a much larger effect on ovarian cancer cell metabolism, while glucose deprivation had a greater effect on ovarian cancer stem cell metabolism. Core metabolites and pathways affected by these perturbations were identified, along with pathways that were unique to cell types or perturbations.<h4>Conclusions</h4>The metabolic responses of an ovarian cancer cell line and its derived isogenic cancer stem cells differ greatly under most conditions, suggesting that these two cell types may behave quite differently in an in vivo tumor microenvironment. While cancer metabolism and cancer stem cells are each promising potential therapeutic targets, such varied behaviors in vivo would need to be considered in the design and early testing of such treatments.
2021-11-05 | MTBLS150 | MetaboLights
Project description:Chemoresistance remains the major barrier to effective ovarian cancer treatment. The molecular features and associated biological functions of this phenotype remain poorly understood. We developed carboplatin resistant cell line models using OVCAR5 and CaOV3 cell lines with the aim of identifying chemoresistance-specific molecular features. Chemotaxis and CAM invasion assays revealed enhanced migratory and invasive potential in OVCAR5 resistant, compared to parental cells lines. Mass spectrometry analysis was used to analyse the metabolome and proteome of these cell lines and was able to separate these populations based on their molecular features. It revealed signalling and metabolic perturbations in chemoresistant cell lines. Comparison with the proteome of patient derived primary ovarian cancer cells grown in culture showed a shared dysregulation of cytokine and type 1 interferon signalling, potentially revealing a common molecular feature of chemoresistance. A comprehensive analysis of a larger patient cohort, including advanced in vitro and in vivo models, promises to help better understand the molecular mechanisms of chemoresistance and associated enhancement of migration and invasion.
2022-08-11 | PXD034246 | Pride