Despite an initial satisfactory response to platinum and taxane-based regimens, approximately 80% of ovarian cancer patients will succumb to chemoresistant recurrent disease. Thus, there is a dire need to understand the mechanism by which tumor cells develop resistance to subsequent therapies after first-line cisplatin treatment.
We previously identified that collagen type XI, alpha 1 (COL11A1) is a novel biomarker associated with poor survival, metastasis, and chemoresistance in ovarian cancer. COL11A1 is expressed in a subset of α-SMA-positive cancer-associated fibroblasts (CAFs) adjacent to tumor cells. COL11A1 expression in peritumoral CAFs increases during ovarian cancer progression, with the highest expression in recurrent tumors. However, the functional significance of stromal COL11A1 in ovarian cancer progression and chemoresistance is largely unknown.
To determine the role of stromal COL11A1 in chemoresistance, we generated COL11A1-overexpressing TRS3 ovarian fibroblasts, co-cultured them with A2780 and OVCAR3 ovarian cancer cells, and measured cancer cell sensitivity to cisplatin. Our data showed that ovarian cancer cells become resistant to cisplatin when cultured in direct contact with COL11A1-overexpressing fibroblasts as well as in fibroblast conditioned media. Furthermore, full-length COL11A1 protein, extracted from A204 cell line, increased cisplatin resistance in ovarian cancer cells, suggesting that COL11A1 is sufficient to induce chemoresistance. Interestingly, culture of cancer cells on full-length COL11A1 protein resulted in increased number of ALDHhigh cancer stem-like cells and activation of Akt, the principal mediator of pro-survival signaling. To further dissect the mechanism by which COL11A1 leads to cisplatin resistance in tumor cells, we performed RNA-seq analysis of tumor cells after COL11A1 overexpression. Our data showed that COL11A1 did not change the levels of genes involved in cisplatin transport and DNA repair pathway in cancer cells, which are well-established mechanisms to confer cisplatin resistance. Rather, COL11A1 increased the expression of pro-inflammatory genes, some of which are known to confer chemoresistance in ovarian cancer. Consistently, our Western data showed that COL11A1 activates NF-kB signaling in cancer cells, a central pathway regulating pro-inflammatory genes. Collectively, our data suggest that COL11A1 contributes to chemoresistance possibly due to an increased survival of ALDHhigh cancer stem-like cells through activation of pro-inflammatory signaling.
Citation Format: Miran Rada, Catherine Eldred, Jessica Sage, Sandra Orsulic and Dong-Joo Cheon. COLLAGEN TYPE XI ALPHA 1 (COL11A1) IS A NOVEL STROMAL MEDIATOR OF CHEMORESISTANCE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-017.