Abstract 1511: Stromal gene signature regulated by TGFβ signaling predicts poor clinical outcome in ovarian cancer .

Abstract

Abstract Despite the clinical and histopathological similarities in initial disease presentation, patients with advanced ovarian cancer rapidly develop chemoresistance and succumb to the disease. In order to identify genes that are associated with poor patient survival, we analyzed microarray datasets of 795 advanced ovarian cancer patients and correlated gene expression levels with clinical data. We identified a 60-gene signature that was strongly associated with poor survival. Many genes in the signature were stromal genes, including POSTN, FN1, COL11A1, COL6A1, COL3A1, LOX, TIMP3, and VCAN. The same stromal signature was enriched in ovarian cancer metastases and in a cisplatin-resistant A2780 human ovarian cancer cell line. Expression of many stromal genes was induced by TGFβ1 and the effect was reversed by A83-01, a potent TGFβ1 inhibitor. Interestingly, we found that ovarian cancer stem cells (CSC) also express TGFβR2 and several TGFβ1-target genes, including COL6A1 and COL3A1, which were previously implicated in cisplatin resistance. Culturing of A2780 cells on collagen substrate resulted in increased cisplatin resistance and expansion of the CSC population. Our results suggest that TGFβ1 signaling induces stromal gene expression and forms a favorable microenvironment for ovarian CSC, thereby leading to cisplatin resistance and poor patient survival. Citation Format: Dong-Joo Cheon, Yunguang Tong, Myung-Shin Sim, Xiaojiang Cui, Dror Berel, Mourad Tighiouart, Wolf Ruprecht Wiedemeyer, Beth Karlan, Sandra Orsulic. Stromal gene signature regulated by TGFβ signaling predicts poor clinical outcome in ovarian cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1511. doi:10.1158/1538-7445.AM2013-1511