Though originally studied as a disease of genetically mutated cells, it is now widely accepted that cancers are evolving ecosystems, in which functionally distinct cell types and subpopulations engage in complex interactions that drive tumor progression and metastasis. Defining the principles that govern the division of labor inside the tumor is an open challenge in cancer biology, with vast implications for the development of novel cancer treatments.
Cells in our body constantly acquire mutations and alterations to their DNA. But these events are usually controlled by various protective mechanisms, and are not sufficient to cause cancer. Tumors expand, evade and metastasize only when these protective mechanisms fail, and normal cells are recruited and reprogrammed to support the growing mass of cancer cells instead of trying to kill it. These reprogrammed cells are collectively termed the tumor microenvironment (TME). Cells of the TME support essential tumor functions, and the tumor cannot survive without them. Importantly, though reprogrammed to support the growing tumor, these cells do not harbor mutations to their DNA. Rather, they are transcriptionally reprogrammed, changing the RNA and the regulating phenotypes and functions they exert. These features make the tumor microenvironment an attractive therapeutic target. Eradicating, or re-educating cells of the microenvironment is expected to inhibit tumor growth, and evolving resistance would be harder in cells that have normal DNA.
Our overarching objective is to define the principles that govern phenotypic plasticity in the TME and to understand how heterogeneity in the TME enables the evolution of aggressive cancer phenotypes. Our hypothesis is that this heterogeneity is driven by activation of a network of stress responses that transcriptionally reprograms cells of the TME. Our aim in this project was to map the transcriptional landscape of the TME and define the network of stress responses activated in different cell types and subpopulations of cells in the TME.
In this project, we made a substantial advance in our understanding of transcriptional programs and stress networks underlying phenotypic plasticity in the TME, and tumor fitness. We focused our studies on cancer-associated fibroblasts (CAFs), the most abundant cell type in many carcinomas. We characterized distinct subset of CAF in the TME, we provided evidence that distinct cancer mutations lead to distinct CAF compositions, we established the central protumorigenic role of the stress-activated transcription factor HSF1 in the TME of multiple carcinomas, and we unraveled a new layer of epigenetic regulation of cancer stroma.
