Peristaltic forces drive tumor cell invasion in colorectal cancer

Mechanical forces are known to influence the progression of cancer; however, the impact of naturally occurring physical forces remains less well understood. With the advent of organ-on-chip (OOC) technology, preclinical models can now incorporate human-relevant physiological forces and allow for more precise investigation of their effects. In this study, we explore how the peristaltic motions of the gut influence the early metastatic spread of colorectal cancer (CRC). Specifically, we use a CRC OOC model consisting of tumor epithelial and endothelial channels separated by a porous membrane to investigate, through live cell imaging and ‘omics-based approaches, how peristaltic compressions enhance the invasiveness of colorectal cancer cells. scRNA-seq analysis revealed that invaded tumor cells exhibited significantly higher expression of mechanosensitive genes compared to non-invaded cells. Among the enriched genes was the mechanosensitive calcium ion channel, PIEZO1. Knockdown of PIEZO1 disrupted YAP1-mediated mechanotransduction and reduced invasive capability. In contrast, exposure to peristaltic contractions enhanced invasiveness. Analysis of publicly available datasets confirmed that elevated tumor mechanosensitive gene expression is associated with poorer clinical outcomes. These findings reveal how physiological mechanical forces drive the invasive behavior of mechanosensitive CRC tumors. An organ-on-chip model demonstrated that physiological peristaltic forces promote colorectal cancer cell invasion by activating mechanosensitive genes associated with poor clinical outcomes in patients with colorectal cancer.