Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.
Nature communications. 2024 Nov 16*** epublish ***
Antti Kiviaho, Sini K Eerola, Heini M L Kallio, Maria K Andersen, Miina Hoikka, Aliisa M Tiihonen, Iida Salonen, Xander Spotbeen, Alexander Giesen, Charles T A Parker, Sinja Taavitsainen, Olli Hantula, Mikael Marttinen, Ismaïl Hermelo, Mazlina Ismail, Elise Midtbust, Maximilian Wess, Wout Devlies, Abhibhav Sharma, Sebastian Krossa, Tomi Häkkinen, Ebrahim Afyounian, Katy Vandereyken, Sam Kint, Juha Kesseli, Teemu Tolonen, Teuvo L J Tammela, Trond Viset, Øystein Størkersen, Guro F Giskeødegård, Morten B Rye, Teemu Murtola, Andrew Erickson, Leena Latonen, G Steven Bova, Ian G Mills, Steven Joniau, Johannes V Swinnen, Thierry Voet, Tuomas Mirtti, Gerhardt Attard, Frank Claessens, Tapio Visakorpi, Kirsi J Rautajoki, May-Britt Tessem, Alfonso Urbanucci, Matti Nykter
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland., Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway., Laboratory of Lipid Metabolism and Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Department of Urology, University Hospitals Leuven, Leuven, Belgium., University College London Cancer Institute, London, UK., Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway., KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium., Prostate Cancer Research Center, Tampere University and TAYS Cancer Center, Tampere, Finland., Department of Pathology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway., Clinic of Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway., Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland., Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK., Molecular Endocrinology Laboratory, Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. ., Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. .