A Soft Matrix Microenvironment Promotes Laterally Spreading Tumors via Oxidative Phosphorylation-Dependent Cell...

Area of Science:

• Gastroenterology
• Molecular Biology
• Cancer Research

Background:

• Laterally spreading tumors (LSTs) are flat, early colorectal lesions often missed endoscopically.
• LSTs present unique clinical challenges due to their distinct lateral growth pattern compared to protruding adenomas (PAs).
• Underlying molecular differences driving LST growth remain poorly understood.

Purpose of the Study:

• To comprehensively profile the molecular signatures, cellular phenotypes, and tumor microenvironments of LSTs, PAs, and normal tissues (NTs).
• To investigate the role of the extracellular matrix and specific molecular pathways in LST development.

Main Methods:

• Single-cell RNA sequencing and spatial transcriptomics on clinical specimens.
• Patient-derived organoid models were utilized.
• Comparative analysis of LSTs, PAs, and NTs.

Main Results:

• LSTs displayed a more malignant phenotype with higher copy number variation (CNV) scores and stronger correlation with colorectal cancer.
• Downregulation of adhesion molecules in LSTs was linked to cytoskeletal changes and enhanced oxidative phosphorylation (OXPHOS).
• LSTs were found in a softer extracellular matrix, promoting OXPHOS and modulating adhesion via the ENTPD1-ADORA2B axis.

Conclusions:

• A mechanochemical model is proposed where a soft matrix, OXPHOS, and cytoskeletal remodeling via ENTPD1-ADORA2B contribute to LST lateral growth and suppressed adhesion.
• These findings offer insights into LST development and identify the ENTPD1-ADORA2B axis as a potential therapeutic target.