Abstract 5314: Prostate club-like cells resist treatment and carry prognostic value in lung and pancreatic adenocarcinoma

Abstract Introduction: The prostate cancer tumor microenvironment (TME) contains various cell type identities. We recently described club-like epithelial cells as a constitutive part of the TME present in tissue regions with increased myeloid-derived suppressor cell infiltration. The origin, exact function, and identity of club-like cells remain unresolved. Methods: Here we used bulk, single-cell, and spatial transcriptomics to characterize club-like cells and their relation towards androgen deprivation therapy. We additionally analyzed multiplex immunofluorescence data for interactions between club-like cells and myeloid-derived suppressor cells. Furthermore, we investigated club-like expression in lung and pancreatic tumors. Results: In the spatial transcriptomics data, club-like enriched regions comprise a mixture of club, hillock, and senescent epithelial cells. Prostate cancer tumors from men treated with androgen deprivation therapy display elevated expression of hillock and senescence, but not the club signature. A high club signature score is associated with improved overall survival in TCGA lung adenocarcinoma (LUAD, HR = 0.59, p = 5.1x10-4), while a high hillock gene signature score indicates worse overall survival in both LUAD (HR = 1.80, p = 9.3x10-5) and pancreatic ductal adenocarcinoma (PDAC, HR = 1.94, p = 1.4x10-3). In PDAC, club-like expression is associated with IL-1β+ myeloid cell interaction. We define IL-1β+ myeloid cells in the prostate single-cell data and demonstrate co-localization with club cells in the spatial transcriptomics data. Finally, we show that epithelial cells from castration-resistant prostate cancer samples have an elevated hillock signature compared to normal prostate and treatment-naïve prostate cancer, suggesting hillock expansion or phenotypic plasticity during disease progression. Conclusion: Our results indicate that the canonical club phenotype arises in response to inflammatory signaling, while closely related hillock cells survive androgen deprivation in prostate cancer and indicate poor overall survival in LUAD and PDAC tumors. Citation Format: Antti Kiviaho, Sini K. Eerola, Heini M. Kallio, Miina Hoikka, Aliisa M. Tiihonen, Iida Salonen, Alexander Giesen, Ebrahim Afyounian, Sini Hakkola, Charles T. Parker, Mikael Marttinen, Mazlina Ismail, Wout Devlies, Teuvo L. Tammela, Teemu J. Murtola, Ian G. Mills, Steven Joniau, Gerhardt Attard, Frank Claessens, Tapio Visakorpi, Alfonso Urbanucci, Kirsi J. Rautajoki, Matti Nykter. Prostate club-like cells resist treatment and carry prognostic value in lung and pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5314.