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Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells

Mikella Robinson, Samuel F Gilbert, Jennifer A Waters, Omar Lujano-Olazaba, Jacqueline Lara, Logan J Alexander, Samuel E Green, Gregory Burkeen, Omid Patrus, Ryne Holmberg, Christine Wang, Carrie D House
doi: https://doi.org/10.1101/2020.09.08.288381
Mikella Robinson
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Samuel F Gilbert
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Jennifer A Waters
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Omar Lujano-Olazaba
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Jacqueline Lara
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Logan J Alexander
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Samuel E Green
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Gregory Burkeen
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Omid Patrus
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Ryne Holmberg
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Christine Wang
1Biology Department, San Diego State University, San Diego, CA 92106 USA
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Carrie D House
1Biology Department, San Diego State University, San Diego, CA 92106 USA
2Moores Cancer Center, University of California San Diego, La Jolla, CA 92037 USA
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  • For correspondence: cdhouse@sdsu.edu
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Abstract

Identification of tumor initiating cells (TICs) has traditionally relied on expression of surface markers such as CD133, CD44, and CD117 and enzymes such as aldehyde dehydrogenase (ALDH). Unfortunately, these markers are often cell type specific and not reproducible across patient samples. A more reliable indication of TICs may include elevated expression of stem cell transcription factors such as SOX2, OCT4, and NANOG that function to support long-term self-renewal, multipotency, and quiescence. RNA-sequencing studies presented here highlight a potential role for SOX2 in cell cycle progression in cells grown as 3-D spheroids, which are more tumorigenic and contain higher numbers of TICs than their 2-D monolayer cultured counterparts. SOX2, OCT4, and NANOG have not been comprehensively evaluated in ovarian cancer cell lines, although their expression is often associated with tumorigenic cells. We hypothesize that SOX2, OCT4, and NANOG will be enriched in ovarian TICs and will correlate with chemotherapy resistance, tumor initiation, and expression of traditional TIC markers. To investigate this hypothesis, we evaluated SOX2, OCT4, and NANOG in a panel of eight ovarian cancer cell lines grown as a monolayer in standard 2-D culture or as spheroids in TIC-enriching 3-D culture. Our data show that the high-grade serous ovarian cancer (HGSOC) lines CAOV3, CAOV4, OVCAR4, and OVCAR8 had longer doubling-times, greater resistance to chemotherapies, and significantly increased expression of SOX2, OCT4, and NANOG in TIC-enriching 3-D culture conditions. We also found that in vitro chemotherapy treatment enriches for cells with significantly higher expression of SOX2. We further show that the traditional TIC marker, CD117 identifies ovarian cancer cells with enhanced SOX2, OCT4, and NANOG expression. Tumor-initiation studies and analysis of The Cancer Genome Atlas (TCGA) suggest a stronger role for SOX2 in ovarian cancer relapse compared with OCT4 or NANOG. Overall, our study clarifies the expression of SOX2, OCT4, and NANOG in TICs from a variety of ovarian cancer cell lines. Our findings suggest that SOX2 expression is a stronger indicator of ovarian TICs with enhanced tumor-initiation capacity and potential for relapse. Improved identification of ovarian TICs will advance our understanding of TIC biology and facilitate the design of better therapies to eliminate TICs and overcome chemotherapy resistance and disease relapse.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 10, 2020.
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Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells
Mikella Robinson, Samuel F Gilbert, Jennifer A Waters, Omar Lujano-Olazaba, Jacqueline Lara, Logan J Alexander, Samuel E Green, Gregory Burkeen, Omid Patrus, Ryne Holmberg, Christine Wang, Carrie D House
bioRxiv 2020.09.08.288381; doi: https://doi.org/10.1101/2020.09.08.288381
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Characterization of SOX2, OCT4 and NANOG in ovarian cancer tumor-initiating cells
Mikella Robinson, Samuel F Gilbert, Jennifer A Waters, Omar Lujano-Olazaba, Jacqueline Lara, Logan J Alexander, Samuel E Green, Gregory Burkeen, Omid Patrus, Ryne Holmberg, Christine Wang, Carrie D House
bioRxiv 2020.09.08.288381; doi: https://doi.org/10.1101/2020.09.08.288381

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