Frequent mesothelial-to-mesenchymal transition in colorectal cancer contributes to an immunosuppressive microenvironment.

Abstract

The mesothelial-to-mesenchymal transition (MMT) is the process by which mesothelial cells transform into fibroblast-like cells and migrate into the stroma. Recently, antigen-presenting cancer associated fibroblasts (apCAFs) have been shown to originate from mesothelial cells undergoing MMT and establish an immunosuppressive microenvironment by inducing regulatory T cells (Tregs). It remains unclear whether MMT occurs universally across various cancer types during peritoneal dissemination as a physiological reaction or if its occurrence depends on the organ of origin and tumor characteristics. This study investigated MMT induction and its significance in primary and peritoneal disseminated lesions of colorectal adenocarcinoma (CRAC) and gastric adenocarcinoma (GAC). Analysis of publicly available single-cell RNA sequence data confirmed the presence of MMT-induced cells in both cancer types. Histopathologically, immunohistochemical studies revealed MMT induction in 75.3% of CRAC and 31.0% of GAC primary lesions, and in 67.6% of CRAC and 20.5% of GAC disseminated lesions. MMT induction was more frequent in CRAC than in GAC, even at the same sites of dissemination. In CRAC, MMT was more frequently observed in tubular than in non-tubular adenocarcinoma. Furthermore, the number of apCAFs and Tregs increased with the degree of MMT induction in disseminated CRAC lesions, showing a positive correlation between their numbers. This study demonstrates that MMT is not merely a physiological reaction to cancer invasion, but is induced by cancer, with its extent varying by different cancer types. The induction of the MMT in disseminated CRAC lesions may play a significant role in establishing an immunosuppressive microenvironment.