Project description
Targeting cancer-associated fibroblasts to improve cancer treatment
Refractory tumours and drug resistance are the main challenges in colon cancer therapeutics. The non-tumour factors affecting therapeutic response and the role of the tumour microenvironment in resistance are poorly understood. The EU-funded antiCAFing project will investigate if activation of mechanotransduction signalling in cancer-associated fibroblasts (CAFs) leads to the generation of refractory tumour microenvironments and therapeutic resistance. The study will use colorectal cancer patient-derived CAFs as a tractable system within organ-on-chip, in vitro and preclinical models of CAF-mediated resistance to systematically elucidate the features conferring CAFs their therapy-resistance properties. It aims to discover CAF biomarkers to identify patients with likely responses to therapeutics and show that targeting mechanotransduction in CAFs increases efficacy in non-responders.
Objective
Refractory tumors and emergence of drug resistance are the most important challenges in cancer therapeutics. The non-cancerous determinants of therapeutic response and particularly the role of the tumor microenvironment (TME) in resistance are poorly understood. I previously described the crucial role of cancer-associated fibroblasts (CAFs) 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. Within therapeutic resistance contexts, I hypothesize that preexistent and therapy-induced aberrant activation of mechanotransduction signaling in CAFs leads to the generation of refractory TMEs affecting cancer cell signaling and the behavior of accessory stromal cells such as endothelial and immune cells. As a result, tumors will present: (i) abnormal vasculature associated with reduced drug perfusion and chemotherapy efficacy; (ii) increased production of pro-survival signals affecting targeted therapy; and (iii) inactivation of cytolytic T cells and reduced responses to immunotherapy. I propose that CAF-based biomarkers will improve our capacity to identify patients most likely to respond to these therapeutics. In addition, targeting mechanotransduction in CAFs will significantly increase efficacy in non-responders. Focusing in colorectal cancer, I will use patient-derived CAFs as a tractable system and organ-on-chip, in vitro and preclinical models of CAF-mediated resistance, and combinatorial chemistry to systematically elucidate the molecular and biological features conferring CAFs their privileged therapy-resistance properties. This will illuminate novel and general mechanisms whereby TME characteristics influence tumorigenesis, and inform the development of refined biomarkers to stratify patients and next generation combinatorial therapies (including anti-CAF therapies) with reduced risk of recurrence.
Fields of science
- natural sciencesbiological sciencescell biologycell signaling
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistance
- medical and health sciencesclinical medicineoncologycolorectal cancer
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- engineering and technologyother engineering and technologiesmicrotechnologyorgan on a chip
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-AG - HORIZON Action Grant Budget-BasedHost institution
28006 Madrid
Spain