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While cancer driver mutations are well documented, their tissue-specific effects remain largely attributed to genetic factors, leaving the biophysical aspects underexplored. Here, we demonstrate that mechanical interactions between newly transformed and wild-type cells are critical in determining survival and growth of HRas\n                    <jats:sup>V12<\/jats:sup>\n                    mutants in human mammary and bronchial epithelia, producing contrasting outcomes in the two tissues. In mammary epithelium, isolated mutants are extruded \u2013 typical of epithelial defense against cancer \u2013 while mutant groups become spatially confined in kinetically arrested, jammed clusters, marked by an actomyosin belt at the interface. In contrast, bronchial epithelium permits persistent spreading of the mutants, which form long protrusions regardless of colony size. Furthermore, oncogenic clusters in the two tissues exhibit distinct biophysical properties, including variations in cell shapes, intracellular pressure, cell-cell tension, and cellular motility. Using a cell shape-tension coupled bi-disperse vertex model, we reveal that interfacial tension at mutant-wild-type boundaries dictates whether mutants are eliminated, restrained, or expanded. Additionally, modulating the heterotypic interfacial tension alters mutant cluster fates. Together, our findings uncover a mechanical basis for tissue-specific oncogenesis by highlighting how interfacial mechanics between mutants and wild-type populations regulate tumor initiation and progression.\n                  <\/jats:p>","DOI":"10.7554\/elife.106893","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T14:31:00Z","timestamp":1756391460000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.106893","source":"Crossref","is-referenced-by-count":2,"title":["Heterotypic interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5400-2211","authenticated-orcid":true,"given":"Amrapali","family":"Datta","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04dese585","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bioengineering, Indian Institute of 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