| Autor: |
Clevenger AJ; Texas A&M University, College Station, United States., Collier CA; Texas A&M University, College Station, United States., Gorley JPM; Texas A&M University, United States., Colijn S; Washington University in St. Louis, United States., McFarlin MK; Texas A&M University, United States., Solberg SC; Texas A&M University, College Station, United States., Kopetz ES; University of Texas MD Anderson Cancer Center, Houston, TX, United States., Stratman AN; Washington University in St. Louis, United States., Raghavan SA; Texas A&M University, College Station, TX, United States. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular cancer research : MCR [Mol Cancer Res] 2024 Nov 01. Date of Electronic Publication: 2024 Nov 01. |
| DOI: |
10.1158/1541-7786.MCR-24-0624 |
| Abstrakt: |
Colorectal cancer (CRC) tumors start as polyps on the inner lining of the colorectum, where they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in CRC cells. However, this malignant mechanotransductive response was confined to select CRC lines that harbored an oncogenic mutation in the KRAS gene. Here, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in CRC. Peristalsis enriched cancer stem cell marker LGR5 in KRAS mutant lines, in a Wnt-ligand-independent manner. Conversely, LGR5 enrichment in wild type KRAS lines exposed to peristalsis were minimal. LGR5 enrichment downstream of peristalsis translated to increased tumorigenicity in vivo. Differences in mechanotransduction was apparent via unbiased gene set enrichment analysis, where many unique pathways were enriched in wild type vs. mutant lines. Peristalsis also triggered β-catenin nuclear localization independent of Wnt-ligands, particularly in KRAS mutant lines. The involvement of KRAS was validated via gain and loss of function strategies. Peristalsis induced β-catenin activation and LGR5 enrichment depended on the activation of the MEK/ERK cascade. Taken together, our results demonstrated that oncogenic KRAS mutations 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. Implications: Oncogenic KRAS empowers colorectal cancer cells to harness the mechanics of colonic peristalsis for malignant gain, independent of other cooperating signals. . |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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