Palmitic Acid Accumulation Activates Fibroblasts and Promotes Matrix Stiffness in Colorectal Cancer

Area of Science:

• Oncology
• Cancer Biology
• Biochemistry

Background:

• Obstructive colorectal cancer (OCRC) is associated with poor prognosis and distinct tumor characteristics.
• Tumor obstruction may be linked to extracellular matrix (ECM) remodeling, involving collagen and proteoglycans.
• OCRC exhibits altered ECM composition, biomechanics, and collagen arrangement compared to non-obstructive tumors.

Purpose of the Study:

• To investigate the role of extracellular matrix (ECM) remodeling in obstructive colorectal cancer (OCRC).
• To identify mechanisms driving ECM alterations and OCRC progression.
• To explore potential therapeutic targets for OCRC.

Main Methods:

• Comparative analysis of ECM composition and biomechanics in OCRC versus non-OCRC samples.
• Assessment of matrix cancer-associated fibroblasts (mCAFs) and their correlation with palmitic acid (PA) levels.
• Investigation of PA's effect on fibroblast activation and ECM remodeling via the NF-κB pathway.
• Drug screening using a natural compound library to identify inhibitors of PA-induced effects.

Main Results:

• OCRC samples showed significant differences in collagen and proteoglycan composition and ECM biomechanics.
• A notable increase in matrix cancer-associated fibroblasts (mCAFs) was observed in OCRC, correlating with palmitic acid (PA) accumulation.
• PA activated the NF-κB pathway in tumor cells, stimulating cytokine secretion that promoted mCAF generation and ECM stiffening.
• Vanillylacetone emerged as a potential inhibitor of PA-induced cytokine secretion and ECM stiffening.

Conclusions:

• Intratumoral PA accumulation is a key driver of ECM alterations and OCRC progression.
• The PA-driven pathway involving NF-κB activation, mCAF generation, and ECM stiffening contributes to obstruction development.
• Targeting the PA axis presents a promising therapeutic strategy for colorectal cancer patients at risk of obstruction.