Oncogenic RAS instructs morphological transformation of human epithelia via differential tissue mechanics
| Autor: | Vito Conte, Helen K. Matthews, Xavier Trepat, José J. Muñoz, Marina Uroz, Giulia Fornabaio, Agata Nyga, Suze Dercksen, Buzz Baum |
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| Přispěvatelé: | Biomedical Engineering, Cell-Matrix Interact. Cardiov. Tissue Reg., ICMS Core, Universitat Politècnica de Catalunya. Departament de Matemàtiques, Universitat Politècnica de Catalunya. LACÀN - Mètodes Numèrics en Ciències Aplicades i Enginyeria |
| Rok vydání: | 2021 |
| Předmět: |
Oncogens
Morphology Multidisciplinary Normal tissue morphology Oncogene RAS Enginyeria biomèdica [Àrees temàtiques de la UPC] Biomecànica Homeòstasi Extrusion process Oncogenes Biology Morfologia (Biologia) Epithelium Cell biology Morphological transformation Epithelial homeostasis medicine.anatomical_structure Transferases Extrusió (Mecànica) medicine Homeostasis Biomechanics Tissue mechanics |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Science Advances, 7(42):eabg6467. American Association for the Advancement of Science (AAAS) UPCommons. Portal del coneixement obert de la UPC Universitat Politècnica de Catalunya (UPC) |
| ISSN: | 2375-2548 |
| Popis: | The loss of epithelial homeostasis and the disruption of normal tissue morphology are hallmarks of tumor development. Here, we ask how the uniform activation oncogene RAS affects the morphology and tissue mechanics in a normal epithelium. We found that inducible induction of HRAS in confined epithelial monolayers on soft substrates drives a morphological transformation of a 2D monolayer into a compact 3D cell aggregate. This transformation was initiated by the loss of monolayer integrity and formation of two distinct cell layers with differential cell-cell junctions, cell-substrate adhesion, and tensional states. Computational modeling revealed how adhesion and active peripheral tension induces inherent mechanical instability in the system, which drives the 2D-to-3D morphological transformation. Consistent with this, removal of epithelial tension through the inhibition of actomyosin contractility halted the process. These findings reveal the mechanisms by which oncogene activation within an epithelium can induce mechanical instability to drive morphological tissue transformation. This work was supported by the Spanish Ministry MICINN/FEDER (grants BFU2016-75101-P and RYC-2014-15559 to V.C., DPI2016-74929-R to J.M., BES-2017-081337 to G.F., and BES-2013-062633 to M.U.), Generalitat de Catalunya (grant no. 2017SGR1278 to J.M.), the IBEC-ICMS Exchange Program fund to A.N. for nanoindentation measurements, and the EMBO long-term fellowship (EMBO ALTF 811-2018) to M.U. H.M. was supported by a CRUK/EPSRC Multi-Disciplinary Project Award (C1529/A23335) and the MRC/UCL Laboratory for Molecular Cell Biology (MC_CF12266). A.N. and B.B. were supported by Cancer Research UK (C1529/A28276). The Spanish Ministry (MICINN) and its funding programs (Severo Ochoa, FPI, and Excelencia) along with the CERCA Program of the Generalitat de Catalunya support research at the IBEC. |
| Databáze: | OpenAIRE |
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