Abstract 3856: Elucidating the role of fibroblasts in CRPC and ADPC progression using 3D engineered prostate cancer tissues

Abstract

Abstract Prostate cancer (PC) currently represents 7.5% of all new cancer cases; notably, the 5-year relative survival rate drops from 100% in localized cases to 30.2% in patients who present with metastases. There are no curative therapies for metastatic PC, and most men develop serial resistance to androgen suppression, resulting in a more aggressive disease state that is much more difficult to mitigate. Fibroblasts have been implicated in cancer progression and are thought to intravasate alongside circulating tumor cells and prime metastatic sites for tumor growth. Our understanding of the precise mechanisms by which they contribute to PC, however, is relatively underdeveloped in comparison to other solid cancer types. Here, we report a three-dimensional (3D) engineered prostate cancer tissue (EPCaT) model comprised of PC-3 castration-resistant (CRPC) or LNCaP androgen-dependent (ADPC) PC cell lines in direct coculture with BJ-5ta fibroblasts. By specifically isolating this cell-cell interaction within a bioinspired poly(ethylene glycol)-fibrinogen (PF) matrix, our EPCaT model introduces the ability to monitor coculture-driven changes at a tissue, cellular, and transcriptomic level. Temporal variations in EPCaT growth, cell and colony morphology, cell populations, and cell-mediated remodeling of the PF matrix were assessed. Changes in bulk transcriptomic expression were also quantified and differentially expressed genes (DEGs) were evaluated between CRPC and ADPC mono- and coculture conditions. Finally, to evaluate the clinical significance of our findings, EPCaTs were evaluated against normal and primary tumor tissue transcriptomic data acquired from the Cancer Genome Atlas (TCGA). In comparison to monoculture EPCaTs, both CRPC- and ADPC-fibroblast coculture conditions resulted in an increase in the number of proliferative cells, morphological features of cancer cell migration, and cell-mediated remodeling of the PF matrix, all of which suggest a more aggressive cell phenotype. DEG and gene ontology analysis revealed coculture-driven changes in genes associated with important tumorigenic processes including ECM organization, angiogenesis, and epithelial cell proliferation and migration. Interestingly, fibroblast coculture had a significantly larger impact on the ADPC transcriptome in comparison to CRPC, suggesting that fibroblasts could play an elevated role in less aggressive disease states. Notable DEGs in ADPC coculture that were also clinically significant in the TCGA tumor versus normal comparison included an overexpression of OR51E2 which has been shown to increase epithelial cell proliferation and participate in the ADPC to CRPC switch, thus exacerbating PC progression. Future studies will augment the pathophysiological relevance of our EPCaT model by including patient-isolated cancer-associated fibroblasts from recurring and non-recurring patients. Citation Format: Nicole L. Habbit, Benjamin Anbiah, Joshita Suresh, Yuan Tian, Luke S. Anderson, Megan L. Davies, Iman Hassani, Taraswi Mitra Ghosh, Balabhaskar Prabhakarpandian, Robert D. Arnold, Elizabeth A. Lipke. Elucidating the role of fibroblasts in CRPC and ADPC progression using 3D engineered prostate cancer tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3856.