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 (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine oncology
- engineering and technology other engineering and technologies microtechnology organ on a chip
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
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Call for proposal
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(opens in new window) ERC-2021-COG
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28006 MADRID
Spain
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