Bioengineered Tumor-Stroma Prostate Cancer In Vitro Models for Screening Therapeutics

IF 3.5 2区生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Biotechnology and Bioengineering Pub Date : 2025-03-13 DOI:10.1002/bit.28971

Maria V. Monteiro, Filipa Moreira-Silva, Matilde Lagarto, Luís P. Ferreira, Carlota Ramalhinho, Iola F. Duarte, Carmen Jerónimo, Vítor M. Gaspar, João F. Mano

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Abstract

Cancer-associated fibroblasts are increasingly recognized to have a high impact on prostate tumor growth and drug resistance. Here, we bioengineered organotypic prostate cancer 3D in vitro models to better understand tumor-stroma interplay, the metabolomic profile underlying such interactions, and their impact on standard-of-care therapeutics performance. The assembly of robust and uniform spheroids was evaluated and compared in monotypic PC-3 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-3 prostate cancer spheroids with reproducible morphology and size. The inclusion of cancer-associated 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 were additionally exploited for screening standard-of-care therapeutics, exhibiting a higher resistance when compared to their monotypic counterparts. Our findings demonstrate that including stromal elements in PC-3 prostate cancer models is crucial for their use as increasingly organotypic testing platforms, being relevant for screening candidate anti-cancer therapeutics and for the discovery of potential combinations with emerging anti-stroma therapies.

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用于筛选治疗的生物工程肿瘤-基质前列腺癌体外模型

癌症相关成纤维细胞越来越被认为对前列腺肿瘤生长和耐药性有重要影响。在这里，我们对器官型前列腺癌3D体外模型进行了生物工程改造，以更好地了解肿瘤-基质相互作用，这种相互作用背后的代谢组学特征，以及它们对标准治疗性能的影响。我们评估并比较了单型PC-3和由健康或恶性间质和前列腺癌细胞组成的异型微肿瘤中坚固而均匀的球体的组装。我们的研究结果表明，前列腺癌基质元素的精确包含对于产生具有可复制形态和大小的健壮的PC-3前列腺癌球体至关重要。癌症相关成纤维细胞的加入促进了更致密的微肿瘤的建立，并表现出主要蛋白的特征性表达。外代谢组学分析也强调了基质细胞对肿瘤模型代谢的影响。优化的异型球体还被用于筛选标准治疗药物，与单型治疗药物相比，它们表现出更高的耐药性。我们的研究结果表明，在PC-3前列腺癌模型中包含基质元素对于它们作为越来越多的器官型测试平台的使用至关重要，与筛选候选抗癌疗法和发现与新兴抗基质疗法的潜在组合相关。

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来源期刊

Biotechnology and Bioengineering 工程技术-生物工程与应用微生物

CiteScore

7.90

自引率

5.30%

发文量

280

审稿时长

2.1 months

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