Oncogenic KRAS Mutations Confer a Unique Mechanotransduction Response to Peristalsis in Colorectal Cancer Cells Institutional Repository Document uri icon

abstract

  • AbstractColorectal cancer (CRC) tumors start as precancerous polyps on the inner lining of the colon or rectum, where they are exposed to the mechanics of colonic peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select CRC lines that harbored an oncogenic mutation in theKRASgene. In this work, therefore, we explored the involvement of activatingKRASmutations on peristalsis-associated mechanotransduction in CRC. Peristalsis enriched the cancer stem cell marker LGR5 inKRASmutant (G13D, etc.) lines, in a Wnt-independent manner. Conversely, LGR5 enrichment in wild typeKRASlines exposed to peristalsis were minimal. LGR5 enrichment downstream of peristalsis translated to increased tumorigenicityin vivoinKRASmutant vs. wild type lines. Differences in mechanotransduction response was additionally apparent via unbiased gene set enrichment analysis, where many unique pathways were enriched in wild type vs. mutant lines, in response to peristalsis. Interestingly, peristalsis also triggered -catenin nuclear localization independent of Wnt, particularly inKRASmutant lines. The central involvement of KRAS in the mechanotransductive responses was validated via gain and loss of function strategies. -catenin activation and LGR5 enrichment downstream of peristalsis converged to the activation of the MEK/ERK kinase cascade, that remains active in cells that harbor oncogenicKRASmutations. Taken together, our results demonstrated that oncogenicKRASmutations conferred a unique peristalsis-associated mechanotransduction response to colorectal cancer cells, resulting in cancer stem cell enrichment and increased tumorigenicity. These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS.

author list (cited authors)

  • Clevenger, A. J., Collier, C. A., Gorley, J., McFarlin, M. K., Solberg, S. C., Kopetz, E. S., Stratman, A. N., & Raghavan, S. A.

complete list of authors

  • Clevenger, Abigail J||Collier, Claudia A||Gorley, John Paul M||McFarlin, Maygan K||Solberg, Spencer C||Kopetz, E Scott||Stratman, Amber N||Raghavan, Shreya A

Book Title

  • bioRxiv

publication date

  • May 2024