BRCA1/2 mutations are well-established hereditary cancer predisposition genes that confer an increased risk of cancer to mutation carriers. These mutations are highly prevalent in high-grade serous ovarian cancer (HGSOC), the most lethal gynecologic malignancy. Preliminary data from the Scherz-Shouval lab indicate that BRCA1-mutant HGSOC tumors exhibit a distinct tumor microenvironment (TME), characterized by enrichment of mesothelial cells and inflammatory cancer-associated fibroblasts (iCAFs), compared with BRCA1 wild-type (WT) tumors.
In addition, BRCA1 mutations are known to reprogram cancer cell metabolism, enhancing glycolysis through loss of c-MYC regulation and leading to increased lactate secretion. Importantly, lactate uptake by stromal cells has been shown to induce an iCAF phenotype in several cancer types, suggesting a potential mechanism of metabolic crosstalk between cancer cells and the TME.
We therefore hypothesize that BRCA1 mutations shape the TME through altered lactate metabolism, a hypothesis that this collaboration aims to visualize using advanced magnetic resonance spectroscopic imaging (MRSI). The collaboration between the Scherz-Shouval and Frydman labs will enable high-resolution mapping of lactate metabolism in HGSOC mouse models and in-vitro systems. This approach will allow us to mechanistically dissect lactate-driven cancer–stroma interactions, with the goal of uncovering new biological insights into BRCA1-mutant cancers that may guide future strategies to target cancer–stroma metabolic crosstalk in HGSOC.
Since September, we have performed several in-vitro studies exploring metabolic differences between BRCA1 WT and mutant cancer cells, laying the groundwork for more complex culture systems that incorporate additional components of the TME.