Autocrine activation of MAPK signaling mediates intrinsic tolerance to androgen deprivation in LY6D prostate cancer cells
Ivana Steiner,
Teresita del N.J. Flores-Tellez,
Renaud Mevel,
Amin Ali,
Pengbo Wang,
Pieta Schofield,
Caron Behan,
Nicholas Forsythe,
Garry Ashton,
Catherine Taylor,
Ian G. Mills,
Pedro Oliveira,
Simon S. McDade,
Dietmar M. Zaiss,
Ananya Choudhury,
Georges Lacaud,
Esther Baena
Affiliations
Ivana Steiner
Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Teresita del N.J. Flores-Tellez
Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Renaud Mevel
Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Amin Ali
Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK; Belfast-Manchester Movember Centre of Excellence, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Pengbo Wang
Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Pieta Schofield
Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Caron Behan
Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Nicholas Forsythe
Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, BT9 7BL Northern Ireland, UK; Belfast-Manchester Movember Centre of Excellence, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Garry Ashton
Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Catherine Taylor
The Christie NHS Foundation Trust, Manchester Academic Health Sciences Centre, M20 4BX Manchester, UK
Ian G. Mills
Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, BT9 7BL Northern Ireland, UK; Belfast-Manchester Movember Centre of Excellence, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK; Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, OX3 9DU Oxford, UK; Department of Clinical Sciences and Centre for Cancer Biomarkers, University of Bergen, 7804 Bergen, Norway
Pedro Oliveira
Department of Pathology, The Christie NHS Foundation Trust, M20 4BX Manchester, UK
Simon S. McDade
Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, BT9 7BL Northern Ireland, UK; Belfast-Manchester Movember Centre of Excellence, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Dietmar M. Zaiss
Department of Immune Medicine, University Regensburg, Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, and Leibniz Institute for Immunotherapy (LIT), 93053 Regensburg, Germany
Ananya Choudhury
The Christie NHS Foundation Trust, Manchester Academic Health Sciences Centre, M20 4BX Manchester, UK; The University of Manchester, Manchester Cancer Research Centre, M20 4BX Manchester, UK; Belfast-Manchester Movember Centre of Excellence, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Georges Lacaud
Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK
Esther Baena
Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK; Belfast-Manchester Movember Centre of Excellence, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK; Corresponding author
Summary: 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 kinase (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 organoid 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.
