Oncogene-Mechanics Axis: KRAS G12C Confers Agility Enabling Malignant Mechano-responses to Peristalsis in Colorectal Cancer

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 and KRAS G12C cancer cells sensed peristalsis via ERK phosphorylation, 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 controls. Using Brillouin microscopy, we discovered that KRAS G12C induced a more agile and deformable mechano-phenotype by lowering intracellular viscosity, a state further amplified by peristalsis. This agility allowed KRAS G12C cancer cells to leverage, rather than resist peristalsis, resulting in LGR5 enrichment and malignant progression. Pharmacologic inhibition of KRAS G12C reversed the mechano-phenotype, while introducing KRAS G12C into healthy cells recapitulated it. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cells mechanical state could be a powerful complement to emerging KRAS-directed therapies. TeaserHow does the guts 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.