Harnessing Stromal Fibroblasts to Reduce Resistance and Improve Colon Cancer Therapeutics

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:

1. Matrix remodeling
2. Cancer cell invasion
3. 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:

1. Abnormal vasculature associated with reduced drug perfusion and chemotherapy efficacy
2. Increased production of pro-survival signals affecting targeted therapy
3. 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.