Abstract IA14: Breaking bad: Cancer-associated fibroblasts are reprogrammed from growth inhibitory to pro-inflammatory and tumor promoting in breast cancer

Abstract

Abstract Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. We previously demonstrated that Cancer-Associated Fibroblasts (CAFs) orchestrate tumor-enhancing inflammation in multiple mouse and human malignancies, including breast cancer. Although breast cancer is one of the major tumor types where CAFs were shown to be tumor promoting, there is no detailed analysis of the dynamic changes in CAFs characteristics and function in correlation with tumor progression. We therefore set out to characterize the dynamic changes in CAFs during progression of mammary carcinogenesis, in a transgenic mouse model of human breast cancer. We profiled the transcriptome of fibroblasts isolated from normal mammary glands, or from mammary glands of transgenic mice at defined tumorigenic stages. Data analysis revealed unique CAF gene signatures that correspond to distinct tumor stages, with only partial overlap between the stages, suggesting co-evolution of the microenvironment with tumorigenic progression. Interestingly, the gene signature of fibroblasts isolated from hyperplastic lesions is inverse to that in CAFs from neoplastic stages, and has a growth inhibitory phenotype, while CAFs from mammary tumors express pro-inflammatory and tumor promoting gene signatures. Moreover, we functionally demonstrate that CAFs isolated from late carcinoma express a gene signature that links tissue damage with tumor-promoting inflammation. To identify tumor-secreted factors capable of reprogramming normal mammary fibroblasts to pro-inflammatory CAFs, we performed a proteomic screen of breast cancer cells secretome, and identified Osteopontin (OPN). Knockdown of OPN in tumor cells in vivo resulted in attenuated stromal activation, reduced immune cell recruitment and inhibition of tumor growth. Taken together, our findings reveal reciprocal crosstalk between fibroblasts and cancer cells which drives CAF reprogramming, to facilitate tumor progression in breast cancer. Citation Format: Yoray Sharon, Nour Ershaid, Yael Raz, Noam Cohen, Metsada Pasmanik-Chor, Tamar Geiger, Neta Erez. Breaking bad: Cancer-associated fibroblasts are reprogrammed from growth inhibitory to pro-inflammatory and tumor promoting in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA14.