The cancer-associated fibroblasts landscape of ovarian BRCA mutated cancer

The tumor microenvironment (TME) constitutes most of the tumor volume in many cancer types and is composed of non-malignant cells and secreted proteins that support tumor progression. Cancer-associated fibroblasts (CAFs) are an essential element of the TME, responsible for immune interactions, secretion of extracellular matrix proteins, chemokines, growth factors, and more. Recent studies done by us and others showed that CAFs are heterogeneous in expression and function and serve multiple roles in the TME. Moreover we have shown that BRCA mutated tumors display different compositions of CAF populations compared to BRCA WT tumors and correlate with a better prognosis.

Ovarian cancer is the most lethal gynecologic cancer yet the options for treatment are limited and 5-year survival rate is 35%. Despite the high prevalence of BRCA mutations in ovarian cancer, their effect on the formation of the TME is largely unexplored.

The goal of this study is to characterize the stromal microenvironment of BRCA WT and mutant ovarian cancer and to assess how this cancer intrinsic mutation affects CAF composition and function. We used multiple existing single-cell mRNA sequencing data to investigate and define the CAF subpopulations of ovarian tumors. We have found four main mesenchymal subpopulations defined by distinct expression signatures. Using this knowledge we will now be able to focus on specific populations, their functions in the TME of BRCA WT and mutant tumors. Uncovering the interaction between cancer mutations and CAFs can facilitate future novel therapies accounting for individual cancer mutations as drivers of specific TMEs.