Stress and mutation dependencies shaping the tumor microenvironment

Tumors initiate through genomic alterations in cancer cells, and progress through reciprocal interactions with non-malignant cells in the tumor microenvironment (TME). Cancer associated fibroblasts (CAFs) are the most abundant cell type in the TME of most carcinomas. CAFs are genomically stable, and transcriptionally rewired by cancer cells to form heterogeneous subpopulations that play diverse and sometimes opposing roles in tumor progression and metastasis. It is well known that oncogenes rewire cancer cells, yet it is not known whether different mutations in the cancer cells lead to differential rewiring of CAFs and contribute to CAF heterogeneity. Moreover, the extent to which CAF rewiring is driven by genomic alterations in the cancer cells versus environmental stresses is not clear.

In my lab we address these questions by combining unbiased mapping and characterization of CAF populations in different carcinomas with a targeted analysis of specific stress responses. In my talk I will discuss recent insights we gained by characterizing the landscape of CAF heterogeneity in BRCA-WT vs BRCA-mutated cancers. I will also share insights and thoughts on CAF epigenetic rewiring and interactions with other cell types in the TME, in particular the immune microenvironment.