Abstract 1991: Enhanced role of the extracellular matrix in ovarian cancer recurrence

Abstract

Abstract Purpose: Despite improvements in care and advancements in the understanding of ovarian cancer (OC) pathobiology and genetic alterations, the survival rate is disappointingly low when compared to that of other types of cancer. One factor contributing to the poor survival rate is the development of chemotherapeutic resistance and a high rate of recurrent tumor growth in the months and years following primary OC treatment. Our objective was to identify potential new therapeutic targets for prevention of recurrence through examination of changes in gene regulation that occur in recurrent versus matched primary tumors. Procedures: We used 16 primary-recurrent tumor pairs from patients with stage III/IV serous epithelial OC from the Duke Gynecologic Oncology Tissue Bank. Illumina Infinium HumanMethylation450 BeadChips and Affymetrix Human Genome U133A arrays were used to quantify methylation and gene expression, respectively. Expression and methylation of POSTN and COL11A1 were analyzed using an independent OC dataset comprising 38 women with <3 years survival and 26 women with >7 years survival, 3 normal ovarian surface epithelium (OSE) and 2 fallopian tube fimbriae epithelium (FTFE) samples. siRNA knockdown of POSTN and COL11A1 in OC cells was followed by expression and proliferation assays. Results: Paired student t tests showed a >2-fold difference for 13 of the 1,569 significantly differentially expressed genes, seven with increased expression in recurrent OC (POSTN, COL11A1, MMP1, MMP13, TNC, ASPN, and EPYC), and six with decreased expression (GATA6, PEG3, SST, MAOB, TSPAN8, and C7). Interestingly, all seven up-regulated genes are involved in extracellular matrix (ECM) functions, an important component of the tumor microenvironment. With an independent OC microarray dataset, we found elevated COL11A1 mRNA in OCs as compared to OSE and FTFE tissues (p<0.05). There are inverse correlations between COL11A1 expression and methylation at five promoter CG sites (R=-0.58 to -0.65, p<0.05). Immunohistochemistry showed higher expression of POSTN and COL11A1 in recurrent OC. Knockdown of POSTN and COL11A1 in OC cell lines led to significantly reduced proliferation (p<0.05). Conclusion: Our findings indicate that the genes involved in extracellular matrix function that contribute to the composition and regulation of the tumor microenvironment play critical roles in OC recurrence, and may offer new therapeutic opportunities. Citation Format: Zhiqing Huang, Brad Foster, Carole Grenier, Gregory Sfakianos, Regina Whitaker, Andrew Berchuck, Susan K. Murphy. Enhanced role of the extracellular matrix in ovarian cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1991. doi:10.1158/1538-7445.AM2017-1991