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Loss of XIST lncRNA promotes stemness and cellular plasticity in ovarian cancer

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE271117 | GEO | 2024/11/05

REPOSITORIES: GEO

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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.

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Loss of XIST lncRNA promotes stemness and cellular plasticity in ovarian cancer

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