Steiner, Ivana and Flores-Tellez, Teresita del N. J. and Mevel, Renaud and Ali, Amin and Wang, Pengbo and Schofield, Pieta and Behan, Caron and Forsythe, Nicholas and Ashton, Garry and Taylor, Catherine and Mills, Ian G. and Oliveira, Pedro and McDade, Simon S. and Zaiss, Dietmar M. and Choudhury, Ananya and Lacaud, Georges and Baena, Esther (2023) Autocrine activation of MAPK signaling mediates intrinsic tolerance to androgen deprivation in LY6D cancer cells. CELL REPORTS, 42 (4): 112377. ISSN 2211-1247,
Full text not available from this repository. (Request a copy)Abstract
The emergence of castration-resistant prostate cancer remains an area of unmet clinical need. We recently identified a subpopulation of normal prostate progenitor cells, characterized by an intrinsic resistance to androgen deprivation and expression of LY6D. We here demonstrate that conditional deletion of PTEN in the murine prostate epithelium causes an expansion of transformed LY6D+ progenitor cells without impairing stem cell properties. Transcriptomic analyses of LY6D+ luminal cells identified an autocrine positive feedback loop, based on the secretion of amphiregulin (AREG)-mediated activation of mitogen-activated protein ki-nase (MAPK) signaling, increasing cellular fitness and organoid formation. Pharmacological interference with this pathway overcomes the castration-resistant properties of LY6D+ cells with a suppression of orga-noid formation and loss of LY6D+ cells in vivo. Notably, LY6D+ tumor cells are enriched in high-grade and androgen-resistant prostate cancer, providing clinical evidence for their contribution to advanced disease. Our data indicate that early interference with MAPK inhibitors can prevent progression of castration-resistant prostate cancer.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PHASE-II TRIAL; PROSTATE-CANCER; GROWTH-FACTOR; EPITHELIAL-CELLS; LUMINAL CELLS; OPEN-LABEL; STEM-CELL; AMPHIREGULIN; RECEPTOR; PTEN; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 10:48 |
| Last Modified: | 30 Jan 2024 10:48 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60543 |
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