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This clinical scenario suggests that surviving drug\u2010resistant tumor cells are dormant or slow\u2010cycling before re\u2010entering a rapid growth phase. Remodeling of the recurrent tumor microenvironment (TME) contributes to high rates of metastasis, but little is known about differences in TME remodeling before therapy and after recurrence. This study explores selection for cisplatin\u2010resistant subpopulations of A549 lung adenocarcinoma cells in culture to derive populations for modeling features of the recurrent TME. A cisplatin dose of 25\u2009\u03bcM killed approximately 80% of the cells while sparing enough cells to allow re\u2010expansion of sufficient cell numbers for downstream experimentation. Expanded cisplatin\u2010resistant derivatives (Cis\u2010R A549) exhibited features of mesenchymal transition (EMT) such as cellular hypertrophy, loss of cell\u2013cell contacts, and upregulation of alpha\u2010smooth muscle actin mRNA. In 3D culture, Cis\u2010R A549 spheroids were loosely aggregated and dysmorphic in comparison to the compact and spherical parent A549 spheroids. The Ki67 index of Cis\u2010R A549 in 2D and 3D spheroid culture was markedly lower than that of parent A549, suggesting a state of pseudo\u2010dormancy with slow cycling. Cis\u2010R A549 upregulated multiple genes associated with the evolution of a more aggressive TME and displayed significantly increased proangiogenic capacity in a microphysiological model of tumor angiogenesis. This study establishes a methodological framework for engineering the recurrent TME with drug\u2010resistant cancer cell line derivatives selected via high\u2010dose exposure in culture. Increased angiogenesis induced by Cis\u2010R A549 suggests that anti\u2010angiogenic therapy may be more beneficial in the setting of recurrent disease following first\u2010line therapies.<\/jats:p>","DOI":"10.1002\/cam4.72267","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:19:11Z","timestamp":1790054351000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cisplatin\u2010Resistant Lung Adenocarcinoma Cells Exhibit Increased Proangiogenic Capacity in a Microphysiological Model of Tumor Neovascularization"],"prefix":"10.1002","volume":"15","author":[{"given":"Elisabet A.","family":"Olsen","sequence":"first","affiliation":[{"name":"Bioinnovation Program Tulane University  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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