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

doi:10.1016/j.celrep.2023.112377

Autocrine activation of MAPK signaling mediates intrinsic tolerance to androgen deprivation in LY6D prostate cancer cells

Cell Rep. 2023 Apr 25;42(4):112377. doi: 10.1016/j.celrep.2023.112377. Epub 2023 Apr 14.

Authors

Ivana Steiner¹, Teresita Del N J Flores-Tellez¹, Renaud Mevel², Amin Ali³, Pengbo Wang¹, Pieta Schofield⁴, Caron Behan⁴, Nicholas Forsythe⁵, Garry Ashton⁴, Catherine Taylor⁶, Ian G Mills⁷, Pedro Oliveira⁸, Simon S McDade⁵, Dietmar M Zaiss⁹, Ananya Choudhury¹⁰, Georges Lacaud², Esther Baena¹¹

Affiliations

¹ Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK.
² Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK.
³ 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.
⁴ Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Macclesfield, UK.
⁵ 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.
⁶ The Christie NHS Foundation Trust, Manchester Academic Health Sciences Centre, M20 4BX Manchester, UK.
⁷ 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.
⁸ Department of Pathology, The Christie NHS Foundation Trust, M20 4BX Manchester, UK.
⁹ 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.
¹⁰ 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.
¹¹ 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. Electronic address: [email protected].

PMID: 37060563
DOI: 10.1016/j.celrep.2023.112377

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 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.

Keywords: CP: Cancer; CP: Cell biology; LY6D; autocrine MAPK signaling; castration resistance; prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgen Antagonists / pharmacology
Androgens* / metabolism
Animals
Cell Adhesion Molecules / metabolism
Cell Line, Tumor
GPI-Linked Proteins / metabolism
Male
Mice
Mitogen-Activated Protein Kinases / metabolism
Prostate / metabolism
Prostatic Neoplasms, Castration-Resistant* / metabolism
Receptors, Androgen / metabolism

Substances

Androgen Antagonists
Androgens
Cell Adhesion Molecules
GPI-Linked Proteins
Mitogen-Activated Protein Kinases
Receptors, Androgen
Ly6d protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding