Transcriptional stress networks underlying phenotypic plasticity in the tumor microenvironment

Tumors are evolving ecosystems, in which malignant and non-malignant cells engage in complex interactions. An overarching challenge in the field of tumor microenvironment is to understand how stromal cells evolve to become protumorigenic. Recently we have shown that a stress response driven by the master transcriptional regulator heat shock factor 1 (HSF1) plays a major role in this evolution, enabling the rewiring of fibroblasts into protumorigenic cancer-associated fibroblasts (CAFs). In my talk I will demonstrate by single-cell transcriptomics that rewiring of CAFs is highly heterogeneous, and that distinct subtypes of CAFs exist in breast cancer. Using an evolutionary theory to infer the tasks performed by these CAF subtypes, we find a division of labor between CAFs performing tasks such as ECM remodeling, biosynthesis, catabolism and growth factor signaling. We further explore the effect of CAF rewiring on cancer phenotypes by targeted dissection of specific stress responses, and the compensatory network of interactions between these stress responses. These findings provide important mechanistic insights into the altered homeostasis of the tumor ecosystem and the complexity of tumor heterogeneity.