Colorectal cancer (CRC) is the most commonly diagnosed cancer and the second cause of cancer death in Europe. CRC patients may be treated with surgery or with systemic treatments including chemo-, targeted or immunotherapy. Despite this spectrum of therapeutic options, refractory tumors and drug resistance are still significant, and represent the most important challenge in CRC treatment. The genetic determinants of response are well-known, but there are still tumors that fail to respond and whose behavior cannot be explained. Tissue composition and non-cancerous cells (i.e. the tumor microenvironment, TME) are important contributors to tumor progression, but their impact in resistance remains poorly understood. Among these, cancer-associated fibroblasts (CAFs) participate in key tumorigenic processes, including matrix remodeling, cancer cell invasion and growth. Importantly, these aggressive CAF phenotypes are controlled by mechanical reprogramming and mechanotransduction pathways. The prominent influence of CAFs in these and other processes suggest that targeting them may represent an innovative alternative for therapeutic intervention that has not been exploited in the clinic, as we still have a limited understanding of the interplay of CAFs and therapy. Revealing the rules that govern CAF-dependent mechanisms of resistance, and identifying novel ways to identify and modulate aggressive CAFs, represents a novel strategy to improve the diagnosis and treatment of cancer.
The overall goal of our project is to systematically dissect how mechanotransduction alters the behavior of CAFs and controls biological processes that influence therapeutic responses in CRC. Specifically, we will investigate how CAFs: (i) contribute to abnormal tumor vascularization and poor anti-cancer drug penetrance; (ii) crosstalk to cancer cells and diminish the effect of targeted chemotherapies; and (iii) alter immune cell composition and influence immunotherapy responses. Moreover, we will also explore whether CAFs with aberrant mechanotransduction present specific epitopes that could be subsequently used for identification and targeted modulation to improve therapeutic responses. Overall, our project will illuminate novel mechanisms whereby TME characteristics influence tumorigenesis and therapeutic responses, and inform the development of refined biomarkers to stratify patients and next generation combinatorial therapies with reduced risk of recurrence.
