NF-kB signaling supports distinct phenotypes necessary for ovarian cancer tumorigenesis

Identification: House, Carrie D.


Description

NF-kB signaling supports distinct phenotypes necessary for ovarian cancer tumorigenesis

Carrie D. House1, Christina M. Annunziata1

1Women’s Malignancies Branch, National Cancer Institute, Bethesda, Maryland

Ovarian cancer is the most lethal gynecological malignancy in the United States with high relapse of chemoresistant disease. We previously showed that a subset of ovarian cancer cells depends on NF-kB signaling, and expression of NF-kB proteins is associated with poor survival. We hypothesize that NF-kB supports a tumor-initiating cell (TIC) program responsible for ovarian cancer relapse. We designed a novel method to enrich for TICs from cell lines and patient samples and showed these cells have higher expression of stem cell markers and NF-kB proteins, are chemoresistant, and are more tumorigenic in nude mice compared to cells cultured as a monolayer. Using inducible shRNAs we show that alternative NF-kB signaling through the RelB transcription factor supports TIC populations by regulating aldehyde dehydrogenase (ALDH), an enzyme highly active in TICs. Spheroid formation, ALDH activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal xenograft models, were significantly inhibited with loss of RelB. We further show that RelB directly regulates the expression of ALDH1A2. Interestingly, classical NF-kB signaling, through the RelA transcription factor, was equally important for tumorigenesis but had no effect on ALDH. RelA was essential for proliferating cells, identified by Ki67 staining, whereas RelB was not. We conclude that NF-kB maintains diverse cellular phenotypes through differential classical and alternative signaling pathways to promote tumorigenesis. Studies are underway to map the global binding distribution of NF-kB factors in TICs and non-TICs. Future studies aim to clarify how classical and alternative NF-kB support heterogeneity in the tumor microenvironment. Given the broad role of NF-kB in cancer biology these findings could significantly impact our understanding of the molecular basis for disease recurrence and therapeutic response.

Funding: CDH: 1K99CA204727; CMA: NCI intramural program (ZIA BC 011054)

Credits

Credits: None available.

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