KLF5 promotes stemness and PARPi resistance through regulation of Vimintin in ovarian cancer
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ABSTRACT:
PROVIDER: PRJNA1045530 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the function of KLF5 in ovarian cancer, we established SKOV3 cell lines in which KLF5 has been knocked down by shRNA.Cells were collected and performed RNA sequencing.
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Project description:Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therapeutic response. Little is known about how stromal fibroblasts respond to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer (OC) and subsequent effects on tumor cells. This is a study to evaluate how CAFs react to PARPis and their potential influence on PARPi resistance in OC. We discovered that OC stromal fibroblasts exhibited intrinsic resistance to PARPis and were further activated after the administration of PARPis. PARPi-challenged fibroblasts displayed a specific secretory profile characterized by increased secretion of CCL5, MIP-3α, MCP3, CCL11, and ENA-78. Mechanistically, increased secretion of CCL5 through activation of the NF-κB signaling pathway was required for PARPi-induced stromal fibroblast activation in an autocrine manner. Moreover, neutralizing CCL5 partly reversed PARPi-induced fibroblast activation and boosted the tumor inhibitory effect of PARPis in both BRCA1/2-mutant and BRCA1/2-wild type xenograft models. Our study revealed that PARPis could maintain and improve stromal fibroblast activation involving CCL5 autocrine upregulation. Targeting CCL5 might offer a new treatment modality in overcoming the reality of PARPi resistance in OC.
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Project description:Cancer cell plasticity is an emerging hallmark of the disease where cells can transition into different cellular states, contributing to tumor heterogeneity. Cellular plasticity is linked to cancer progression, treatment resistance, and relapse. Cancer Stem Cells (CSCs) play an important role in cancer cell plasticity, and molecular factors contributing to stemness maintenance are still poorly understood. Here, we investigate the role of XIST (X-inactive specific transcript) long noncoding RNA (lncRNA) in ovarian cancer cellular plasticity. We perform in silico and in vitro analyses to better understand its function. Our findings demonstrate a significant downregulation of XIST in ovarian tumors. cancer patients.Tumors with low XIST expression have higher stemness index and decreased overall survival. This reduction is associated with an increased stemness in tumors with XIST index and decreased overall survival rates. XIST knockdown (KD) in ovarian cancer cell lines increases stem cell population. Transcriptomic data show that low XIST expression correlates with the upregulation of the stem cell-specific pathways MYC and MTOR, as well as the metabolic pathway OXPHO. Our study also demonstrates that XIST KD increases specifically mesenchymal cancer stem cell (MCSC) population. Finally, ovarian cancer cells with XIST KD show higher plasticity under hypoxic conditions by transitioning into Epithelial Cancer Stem CellsCell (ECSC). Our data reveal that XIST loss induces CSC enrichment, leading to higher cellular plasticity. These findings highlight the important role of XIST in protecting cell identity in ovarian cancer and open the door to new therapeutic approaches for patients with low XIST expression
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Project description:Cancer stem cells (CSCs) are key players in cancer progression, immune evasion, drug resistance, and recurrence, particularly in ovarian cancer. Mitochondria-associated membranes (MAMs) are dynamic structures linking mitochondria and the endoplasmic reticulum, essential for cellular processes. Whether MAMs supports CSCs and the underlying mechanisms remain largely unknown. Here, we unveil that CPT1A is highly expressed in ovarian cancer stem cells (OCSCs) and is essential for stemness maintenance. CPT1A facilitates stemness maintenance by regulating lipid desaturation in ovarian cancer. Further studies confirmed that CPT1A enhances SREBP1 cleavage and nuclear translocation, thereby upregulating SCD1 expression and promoting lipid desaturation in OCSCs. Furthermore, MAMs are found to be critical for SREBP1 activation. Mechanistic studies have shown that CPT1A promotes mitochondrial fission factor (MFF) succinylation (succK-MFF) through its lysine succinyltransferase (LSTase) activity, with succK-MFF being crucial for MAMs formation and SREBP1 activation. Additionally, inhibiting the LSTase activity of CPT1A with Glyburide reduced OCSCs' stemness and enhanced cisplatin's anti-tumor effects against ovarian cancer both in vitro and in vivo. Together, our studies reveal the importance of CPT1A's LSTase activity in MAMs formation and OCSCs' stemness maintenance, providing potential targets and therapeutic strategies for ovarian cancer treatment.
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Project description:We leverage RNA sequencing to identify the transcriptional changes assocaited with several experimental conditions that induce a stemness phenotype in the ovarian surface epithelium, including spheroid culture, Snail overexpression, and BRCA1 deletion
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Project description:Ovarian cancer (OC) is the most lethal gynecological cancer due to its late diagnosis and, importantly, its high rate of chemoresistance. Hypoxia in solid tumors is an important source of chemoresistance that can determine poor patient prognosis. Such chemoresistance relies on the presence of cancer stem cells (CSCs), and hypoxia promotes their generation through transcriptional activation by HIF transcription factors. We use OC cell lines, xenograft models, OC patient samples, transcriptional databases, iPSCs and ATAC-seq. We show here that hypoxia induces the formation of ovarian CSCs through transcriptional activation of the PLD2 gene encoding phospholipase D2. HIF-1 activates PLD2 transcription through hypoxia response elements located within PLD2 promoter and an intronic enhancer. PLD2 overexpression leads to similar effects than hypoxia, increasing CSC-like features, stemness gene expression and enhancing cell reprogramming in OC cells, as well as chromatin accessibility around stemness genes detected by ATAC-seq. Conversely, PLD2 depletion in hypoxia partially suppresses these effects, indicating that PLD2 is a major determinant of hypoxia-induced CSC generation in OC. Indeed, PLD2 expression is high in OC patients leading to poor survival and a transcriptional switch in the genes related to the response to hypoxia and stemness. Finally, we demonstrate that PLD2 overexpression provokes resistance to platinum-based chemotherapy and that combination of cisplatin with pharmacological inhibition of PLD2 suppresses such resistance. Altogether, our work highlights the importance of the HIF-1-PLD2 axis for CSC generation and chemoresistance in OC and proposes an alternative treatment for patients with high PLD2 expression.
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