Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance.
Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.
Vancouver Prostate Centre, Vancouver, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Mannan
M
Nouri
Vancouver Prostate Centre, Vancouver, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Josselin
J
Caradec
Vancouver Prostate Centre, Vancouver, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Amy Anne
AA
Lubik
Vancouver Prostate Centre, Vancouver, Canada.
Na
N
Li
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
Brett G
BG
Hollier
GenomeDX Biosciences, Vancouver, Canada.
Mandeep
M
Takhar
Vancouver Prostate Centre, Vancouver, Canada.
Manuel
M
Altimirano-Dimas
Drug Discovery & Biomedical Sciences, South Carolina College of Pharmacy, Columbia, South Carolina, USA.
Mengqian
M
Chen
Vancouver Prostate Centre, Vancouver, Canada.
Mani
M
Roshan-Moniri
Vancouver Prostate Centre, Vancouver, Canada.
Miriam
M
Butler
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
Melanie
M
Lehman
Vancouver Prostate Centre, Vancouver, Canada.
Jennifer
J
Bishop
Vancouver Prostate Centre, Vancouver, Canada.
Sarah
S
Truong
Vancouver Prostate Centre, Vancouver, Canada.
Shih-Chieh
SC
Huang
Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, Canada.
Dawn
D
Cochrane
Vancouver Prostate Centre, Vancouver, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Michael
M
Cox
Vancouver Prostate Centre, Vancouver, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Colin
C
Collins
Vancouver Prostate Centre, Vancouver, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Martin
M
Gleave
GenomeDX Biosciences, Vancouver, Canada.|GenomeDX Biosciences, San Diego, California, USA.
Nicholas
N
Erho
GenomeDX Biosciences, Vancouver, Canada.
Mohamed
M
Alshalafa
GenomeDX Biosciences, Vancouver, Canada.|GenomeDX Biosciences, San Diego, California, USA.
Elai
E
Davicioni
Vancouver Prostate Centre, Vancouver, Canada.|Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
Colleen
C
Nelson
Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada.
Sheryl
S
Gregory-Evans
Department of Urology, Mayo Clinic, Rochester, Minnesota, USA.
R Jeffrey
RJ
Karnes
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Robert B
RB
Jenkins
Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Eric A
EA
Klein
Vancouver Prostate Centre, Vancouver, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Ralph
R
Buttyan
D000818:Animals; D015153:Blotting, Western; D054338:Cell Transdifferentiation / Q000502:physiology*; D065150:Cellular Reprogramming / Q000502:physiology*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D015027:Zebrafish
cancer stem cell; hormone resistance; neural crest; neuroendocrine transdifferentiation; prostate cancer