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Due to the somatic mosaicism, the affected tissues comprise a mixture of mutant and wild-type cells. However, how PIK3CA mutated ADSCs influence adjacent wild-type cells in macrodactyly remains poorly understood. In this study, we utilized coculture systems to investigate the effects of macrodactylous adipose-derived stem cells (Mac-ADSCs) on normal ADSCs, fibroblasts (FBs), and vascular endothelial cells (VECs). Our study demonstrated that activating PIK3CA mutations in Mac-ADSCs promotes the proliferation, migration, invasion, adipogenesis, and angiogenesis of wild-type ADSCs, FBs and VECs. Furthermore, using RNA sequencing and cytokine arrays, we revealed that these effects are primarily mediated by various secreted paracrine cytokines. These findings demonstrated that activating PIK3CA mutation alters the paracrine characteristics of Mac-ADSCs and reshapes the microenvironment of macrodactyly, driving adjacent wild-type cells to exhibit mutant-like phenotypes. Targeting PIK3CA with BYL-719 could influence the progression of macrodactyly by inhibiting the paracrine signaling of Mac-ADSCs.<\/jats:p>","DOI":"10.1038\/s41419-025-07795-7","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T02:58:38Z","timestamp":1751338718000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Activating PIK3CA mutations in adipose-derived stem cells drive mutant-like phenotypes of wild-type cells in macrodactyly"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0362-6688","authenticated-orcid":false,"given":"Xiao","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongkang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiping","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2999-7142","authenticated-orcid":false,"given":"Hailei","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7940-1223","authenticated-orcid":false,"given":"Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"7795_CR1","doi-asserted-by":"publisher","first-page":"982.e1","DOI":"10.1016\/j.jhsa.2020.03.002","volume":"45","author":"J Wu","year":"2020","unstructured":"Wu J, Tian G, Ji Y, Higgins JP, Lee WPA. 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