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Here, we bioengineered organotypic prostate cancer 3D in vitro models to better understand tumor\u2010stroma interplay, the metabolomic profile underlying such interactions, and their impact on standard\u2010of\u2010care therapeutics performance. The assembly of robust and uniform spheroids was evaluated and compared in monotypic PC\u20103 and heterotypic microtumors comprised of either a healthy or malignant stroma and prostate cancer cells. Our findings demonstrate that the precise inclusion of prostate cancer stromal elements is crucial to generating robust PC\u20103 prostate cancer spheroids with reproducible morphology and size. The inclusion of cancer\u2010associated fibroblasts promoted the establishment of more compact microtumors exhibiting characteristic expression of major proteins. Exometabolomic profile analysis also highlighted the impact of stromal cells on tumor models metabolism. The optimized heterotypic spheroids\u00a0were additionally exploited for screening standard\u2010of\u2010care therapeutics, exhibiting a higher resistance when compared to their monotypic counterparts. Our findings demonstrate that including stromal elements in PC\u20103 prostate cancer models is crucial for their use as increasingly organotypic testing platforms, being relevant for screening candidate anti\u2010cancer therapeutics and for the discovery of potential combinations with emerging anti\u2010stroma therapies.<\/jats:p>","DOI":"10.1002\/bit.28971","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T01:55:28Z","timestamp":1741917328000},"page":"1541-1553","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Bioengineered Tumor\u2010Stroma Prostate Cancer In Vitro Models for Screening Therapeutics"],"prefix":"10.1002","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4963-6267","authenticated-orcid":false,"given":"Maria V.","family":"Monteiro","sequence":"first","affiliation":[{"name":"Department of Chemistry, CICECO\u2014Aveiro Institute of 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