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The role of RAS oncogenes in controlling epithelial mechanics
Agata Nyga1, Sushila Ganguli2, Helen K Matthews3
1Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
Abstract:
Mutations in RAS are key oncogenic drivers and therapeutic targets. Oncogenic Ras proteins activate a network of downstream signalling pathways, including extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K), promoting cell proliferation and survival. However, there is increasing evidence that RAS oncogenes also alter the mechanical properties of both individual malignant cells and transformed tissues. Here we discuss the role of oncogenic RAS in controlling mechanical cell phenotypes and how these mechanical changes promote oncogenic transformation in single cells and tissues. RAS activation alters actin organisation and actomyosin contractility. These changes alter cell rheology and impact mechanosensing through changes in substrate adhesion and YAP/TAZ-dependent mechanotransduction. We then discuss how these changes play out in cell collectives and epithelial tissues by driving large-scale tissue deformations and the expansion of malignant cells. Uncovering how RAS oncogenes alter cell mechanics will lead to a better understanding of the morphogenetic processes that underlie tumour formation in RAS-mutant cancers.
Insights
RAS oncogenes alter cell mechanics, affecting actin organization and contractility. These mechanical changes drive cell proliferation and tissue deformation in cancer development.
Area of Science:
- Oncology
- Cell Biology
- Biophysics
Background:
- RAS mutations are central drivers of cancer and targets for therapy.
- Oncogenic Ras proteins activate signaling pathways like ERK and PI3K, promoting cell growth and survival.
- Emerging evidence links RAS oncogenes to altered mechanical properties of cancer cells and tissues.
Purpose of the Study:
- To explore the role of oncogenic RAS in regulating cellular mechanical phenotypes.
- To understand how RAS-induced mechanical changes contribute to oncogenic transformation in single cells and tissues.
Main Methods:
- Analysis of RAS activation effects on actin organization and actomyosin contractility.
- Investigation of changes in cell rheology, substrate adhesion, and mechanosensing pathways (YAP/TAZ).
- Examination of how these mechanical alterations influence collective cell behavior and tissue-level deformations.
Main Results:
- RAS activation modifies actin cytoskeleton organization and actomyosin contractility.
- Altered cell mechanics impact cell rheology and mechanosensing.
- These changes facilitate tissue deformation and malignant cell expansion in collective settings.
Conclusions:
- Understanding RAS-mediated mechanical alterations is crucial for comprehending tumor formation in RAS-mutant cancers.
- Investigating cell mechanics provides insights into the morphogenetic processes underlying cancer progression.
- Targeting mechanical pathways may offer novel therapeutic strategies for RAS-driven cancers.
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