Stress networks underlying phenotypic plasticity and tumor fitness 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 are rewired 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). Here we explore the heterogeneity of CAF rewiring and the role of stress responses in enabling this heterogeneity.

We demonstrate by single-cell transcriptomics of mouse tumors that CAF rewiring is highly heterogeneous, and that distinct subtypes of CAFs exist in breast cancer. These cluster into two major subtypes, the relative abundance of which changes with tumor progression and metastasis and correlates with disease outcome in patients. We further explore the effect of CAF rewiring on cancer phenotypes by targeted dissection of specific stress responses, and unravel a striking effect of stromal HSF1 on extracellular matrix (ECM) assembly. Moreover, we find crosstalk between the ER stress response and the stromal HSF1 program. These findings provide important mechanistic insights into the altered homeostasis of the tumor ecosystem and the complexity of tumor heterogeneity.