Abstract
Simple SummarySOX2, OCT4, and NANOG are enriched in ovarian cancer spheroids and correlate with tumor-initiating cell markers, CD117 and ALDH/CD133. SOX2, relative to OCT4 or NANOG, is a stronger indictor of chemoresistance, tumor-initiation, and recurrent disease. Including SOX2 in evaluation of ovarian cancer TICs may improve reliability of TIC markers and our understanding of mechanisms of relapse.The identification of tumor-initiating cells (TICs) has traditionally relied on surface markers including CD133, CD44, CD117, and the aldehyde dehydrogenase (ALDH) enzyme, which have diverse expression across samples. A more reliable indication of TICs may include the expression of embryonic transcription factors that support long-term self-renewal, multipotency, and quiescence. We hypothesize that SOX2, OCT4, and NANOG will be enriched in ovarian TICs and may indicate TICs with high relapse potential. We evaluated a panel of eight ovarian cancer cell lines grown in standard 2-D culture or in spheroid-enriching 3-D culture, and correlated expression with growth characteristics, TIC marker expression, and chemotherapy resistance. RNA-sequencing showed that cell cycle regulation pathways involving SOX2 were elevated in 3-D conditions. HGSOC lines had longer doubling-times, greater chemoresistance, and significantly increased expression of SOX2, OCT4, and NANOG in 3-D conditions. CD117+ or ALDH+/CD133+ cells had increased SOX2, OCT4, and NANOG expression. Limiting dilution in in vivo experiments implicated SOX2, but not OCT4 or NANOG, with early tumor-initiation. An analysis of patient data suggested a stronger role for SOX2, relative to OCT4 or NANOG, for tumor relapse potential. Overall, our findings suggest that SOX2 may be a more consistent indicator of ovarian TICs that contribute to tumor repopulation following chemotherapy. Future studies evaluating SOX2 in TIC biology will increase our understanding of the mechanisms that drive ovarian cancer relapse.
Highlights
High Grade Serous Ovarian Cancer (HGSOC) is the most lethal gynecological malignancy in women
We showed that SOX2, OCT4 and NANOG are consistently enriched in HGSOC lines cultured in 3-D, and that their expression correlates with genes encoding traditional tumor-initiating cells (TICs) markers
An analysis of RNA-sequencing data identified 10,222 significantly differentially expressed genes (DEGs) in OV90 cells cultured as spheroids in 3-D conditions, relative to OV90 cells cultured as a monolayer in 2-D conditions (Figure 1A, GEO accession number GSE158949)
Summary
High Grade Serous Ovarian Cancer (HGSOC) is the most lethal gynecological malignancy in women. Ovarian cancer recurrence may involve a small population of tumor-initiating cells (TICs) that can resist chemotherapy and efficiently repopulate tumors. The identification of ovarian TICs has traditionally relied on a combination of cell surface proteins, mainly CD133, CD44, and CD117, as well as the activity of aldehyde dehydrogenase (ALDH) enzymes [9,10,11,12]. Ovarian cancer cells have heterogeneous expression of TIC markers that are often cell-line or patient specific. Previous studies showed that SOX2 [13] or ALDH [14], CD133, and CD117 [10] gene expression levels varied across cell lines and patient samples. The genetic heterogeneity of ovarian cancer, as well as the disease stage and/or tissue origin for subsets of ovarian TICs, contribute to the expression of different markers [7,15,16]
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