A Study on the Role of Cancer-Associated Fibroblast- derived COMP in Tumor Growth and Therapeutic Resistance in Colorectal Cancer

Abstract

The tumor microenvironment (TME) orchestrates colorectal cancer (CRC) progression and therapeutic resistance, yet the specific functional contributions of cancer-associated fibroblasts (CAFs)—a dominant stromal component—remain incompletely defined. Although CAF heterogeneity is increasingly recognized, the precise molecular effectors secreted by distinct CAF subpopulations to limit chemotherapeutic efficacy have been poorly understood. Here, we identify Cartilage Oligomeric Matrix Protein (COMP) as a previously unrecognized, myofibroblast CAF (mCAF)-specific matricellular factor that drives tumor growth and drug resistance. Through integrated single-cell and bulk RNA sequencing, we map COMP expression predominantly to the fibroblast compartment of the colorectal TME. Subsequent validation confirms mCAFs as the exclusive cellular source, distinct from inflammatory or antigen-presenting CAF subsets. Mechanistically, we demonstrate that mCAF-derived COMP functions as a potent paracrine ligand that engages the CD36 receptor on CRC cells. This interaction triggers robust activation of the MEK/ERK signaling cascade, thereby fueling cancer cell proliferation and, crucially, conferring resistance to 5-fluorouracil (5-FU), the backbone of standard chemotherapy. Collectively, our findings unmask the mCAF–COMP–CD36 signaling loop as a fundamental driver of CRC malignancy, highlighting mCAF-derived COMP as both a predictive biomarker and a promising therapeutic target to overcome chemoresistance.