Harnessing Stromal Fibroblasts to Reduce Resistance and Improve Colon Cancer Therapeutics
This project aims to understand how cancer-associated fibroblasts influence drug resistance in colorectal cancer, using mechanotransduction pathways to develop biomarkers and improve therapeutic efficacy.
Projectdetails
Introduction
Refractory tumors and the emergence of drug resistance are the most important challenges in cancer therapeutics. The non-cancerous determinants of therapeutic response, particularly the role of the tumor microenvironment (TME) in resistance, are poorly understood.
Role of Cancer-Associated Fibroblasts
I previously described the crucial role of cancer-associated fibroblasts (CAFs) in key tumorigenic processes, including:
- Matrix remodeling
- Cancer cell invasion
- Growth
Importantly, these aggressive CAF phenotypes are controlled by mechanical reprogramming and mechanotransduction pathways.
Hypothesis on Mechanotransduction Signaling
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.
- This affects cancer cell signaling and the behavior of accessory stromal cells such as endothelial and immune cells.
As a result, tumors will present:
- Abnormal vasculature associated with reduced drug perfusion and chemotherapy efficacy
- Increased production of pro-survival signals affecting targeted therapy
- Inactivation of cytolytic T cells and reduced responses to immunotherapy
Proposed Solutions
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.
Research Focus
Focusing on colorectal cancer, I will use:
- Patient-derived CAFs as a tractable system
- Organ-on-chip, in vitro, and preclinical models of CAF-mediated resistance
- Combinatorial chemistry
These approaches will systematically elucidate the molecular and biological features conferring CAFs their privileged therapy-resistance properties.
Expected Outcomes
This research will illuminate novel and general mechanisms whereby TME characteristics influence tumorigenesis. It will also inform the development of refined biomarkers to stratify patients and next-generation combinatorial therapies (including anti-CAF therapies) with reduced risk of recurrence.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 1.999.826 |
Totale projectbegroting | € 1.999.826 |
Tijdlijn
Startdatum | 1-9-2022 |
Einddatum | 31-8-2027 |
Subsidiejaar | 2022 |
Partners & Locaties
Projectpartners
- AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICASpenvoerder
Land(en)
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Deciphering the dynamic-plasticity and heterogeneity of cancer-associated fibroblasts
DynamHet aims to uncover the origins and dynamics of cancer-associated fibroblast heterogeneity to develop targeted therapies that reprogram CAFs for improved cancer treatment.
Targeted Re-engineering of the Tumor Matrix to Advance Immunotherapy
This project aims to disrupt the pro-fibrotic loop in pancreatic cancer using engineered biomimetics to enhance immune therapy efficacy by normalizing the tumor microenvironment.
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This project aims to develop an innovative in vivo platform to study tumor fibrosis and improve targeted cancer therapies by mimicking the fibrotic microenvironment of breast cancer.
Organ and mutation dependencies shaping the tumor microenvironment
This project aims to analyze the tumor microenvironments of BRCA-driven cancers across four organs to identify common design principles for developing targeted therapies.
Reprogramming of Tumor Stroma to Enhance Cancer Immunotherapy
This project aims to enhance cancer immunotherapy effectiveness in solid tumors by targeting tumor-activated mesenchymal stromal cells within the immunosuppressive tumor microenvironment.
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