Prostaglandin E2 facilitates reciprocal crosstalk between intestinal smooth muscle tissue and epithelium in tumor development

Colorectal cancer arises from intestinal epithelial cells and is driven by the accumulation of aberrant signaling events that disrupt intestinal stem cell (ISC) homeostasis. While stromal regulation of the ISC niche is increasingly recognized, the contribution of the underlying/adjacent smooth muscle tissue (SMT) remains poorly characterized. In particular, the potential crosstalk between normal or tumoral epithelium and the SMT is largely unexplored. Here, we investigate the ability of the SMT in modulating normal and tumorigenic epithelial biology, and the impact of the tumoral epithelium on the underlying SMT. Mechanistically, by using imaging analyses, transcriptomics, and mass spectrometry, we identify the SMT-derived factor Prostaglandin E2 (PGE2) as the key driver of epithelial dedifferentiation, promoting YAP transcriptional activation, organoid enlargement, and spheroid morphology in intestinal epithelial organoids following SMT supernatant exposure. Conversely, we show that non-invasive tumoral epithelium induces significant changes in the underlying SMT. Tumor-associated SMT shows structural remodeling, inflammation, and reduced muscle fitness. Furthermore, we detected increased prostaglandin signaling, including upregulation of PGE2 synthase Ptgs1 (COX1), in the SMT underneath the epithelial tumor. Our results reveal a communication between the tumoral epithelium and the underlying SMT prior to metastasis, which could be a facilitating step for tumoral extramural progression. Taken together, these findings highlight a novel tumor-stroma interaction.