Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

The tumor microenvironment (TME) is a challenging environment where cells must cope with stressful conditions such as fluctuating pH levels, hypoxia, and free radicals. In response, stress pathways are activated, which can both promote and inhibit tumorigenesis. In this study, we set out to characterize the stress response landscape across four carcinomas: breast, pancreas, ovary, and prostate tumors, focusing on five pathways: Heat shock response, oxidative stress response, unfolded protein response, hypoxia stress response, and DNA damage response. Using a combination of experimental and computational methods, we create an atlas of the stress response landscape across various types of carcinomas. We find that stress responses are heterogeneously activated in the TME, and highly activated near cancer cells. Focusing on the non-immune stroma we find, across tumor types, that NRF2 and the oxidative stress response are distinctly activated in immune-regulatory cancer-associated fibroblasts and in a unique subset of cancer associated pericytes. Our study thus provides an interactome of stress responses in cancer, offering new ways to intersect survival pathways within the tumor, and advance cancer therapy.