Oncogene-mechanics axis: KRAS G12C confers agility enabling malignant mechano-responses to peristalsis in colorectal cancer

Abstract Oncogene activity and mechanical forces individually and collectively drive colorectal cancer, yet the integration of these signals is unknown. We used a patented peristalsis bioreactor to determine how oncogenic KRAS G12C mutations alter the cellular response to colonic peristalsis. Although both healthy intestinal cells (HIEC-6) and KRAS G12C cancer cells (SW837) sensed peristalsis via ERK phosphorylation (1.7-4.7X increase), their mechano-responses diverged significantly. Peristalsis triggered a 9-fold enrichment of LGR5 + cancer stem cells in KRAS G12C cancer cells, an effect absent in healthy HIEC-6 controls. Using Brillouin microscopy, we discovered that KRAS G12C possessed a mechanically primed state exhibiting 9% reduction in Brillouin Full Width at Half Maximum, indicative of lower intracellular viscosity. Peristalsis further decreased intracellular viscosity in KRAS G12C cells by 11.9%, accompanied by pronounced cell elongation, whereas HIEC-6 maintained viscoelastic homeostasis. This KRAS-dependent mechanical agility enabled KRAS G12C cancer cells to leverage, rather than resist peristalsis, resulting in LGR5 enrichment and malignant progression. Pharmacologic KRAS G12C inhibition with sotorasib reduced LGR5 + cells by 50% under peristalsis, reversing the malignant mechanotype. Conversely, introducing KRAS G12C into HIEC-6 disrupted their mechanical homeostasis and significantly increased LGR5, recapitulating the KRAS-dependent mechano-phenotype. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cell’s mechanical state could be a powerful complement to emerging KRAS-directed therapies. Teaser How does the gut’s movement fuel cancer? We report a novel oncogenic KRAS-mechanics axis, where KRAS G12C mutations lower cancer cell viscosity, conferring agility and deformability. This allows cancer cells to leverage colonic peristalsis resulting in cancer stem cell enrichment. Cells transform physical forces associated with peristalsis into a powerful driver of tumor progression.