Therapy-induced senescence of cancer-associated fibroblasts determines survival in rectal cancer

Standard therapy of rectal cancer comprises a combination of local radio- and systemic chemotherapy prior to surgery. Despite comparable tumor morphology and stage the outcome of such neoadjuvant therapy is heterogeneous and the underlying factors that define therapy response are unknown. Here we demonstrate that cancer-associated fibroblasts (CAFs) rather than tumor cells themselves have major impact on therapy response and survival in a novel pre-clinical in vivo model of rectal cancer as well as in patients. We show that irradiation of tumors increases DNA damage further in inflammatory CAFs causing them to undergo a p53-dependent senescence program, which is associated with the secretion of various extracellular matrix components that strongly promote therapy resistance and progression. Administration of venetoclax (senolytics) renders therapy-resistant mice sensitive to irradiation. Collectively, we demonstrate how inflammatory polarization of CAFs affects cancer therapy and identify IL-1 signaling as an attractive target to repolarize CAFs in neoadjuvant therapy of rectal cancer. Overall design: Total of 104 patients RNA samples (pre-therapeutic biopsies) belonging to patients of pathological complete and non complete response post radiotherapy. Addiotional 12 RNA samples from post chemo-RT surgical materials of RCA patients.