Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance
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Mannan Nouri1,2,*, Josselin Caradec1,2,*, Amy Anne Lubik1,2,*, Na Li1, Brett G. Hollier3, Mandeep Takhar4, Manuel Altimirano-Dimas1, Mengqian Chen5, Mani Roshan-Moniri1, Miriam Butler1, Melanie Lehman3, Jennifer Bishop1, Sarah Truong1, Shih-Chieh Huang1, Dawn Cochrane6, Michael Cox1,2, Colin Collins1,2, Martin Gleave1,2, Nicholas Erho4,7, Mohamed Alshalafa4, Elai Davicioni4,7, Colleen Nelson1,3, Sheryl Gregory-Evans8, R. Jeffrey Karnes9, Robert B. Jenkins10, Eric A. Klein11, Ralph Buttyan1,2
1Vancouver Prostate Centre, Vancouver, Canada
2Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
3Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
4GenomeDX Biosciences, Vancouver, Canada
5Drug Discovery & Biomedical Sciences, South Carolina College of Pharmacy, Columbia, South Carolina, USA
6Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, Canada
7GenomeDX Biosciences, San Diego, California, USA
8Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
9Department of Urology, Mayo Clinic, Rochester, Minnesota, USA
10Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
11Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
*These authors contributed equally to this work
Ralph Buttyan, email: [email protected]
Keywords: prostate cancer, cancer stem cell, neural crest, neuroendocrine transdifferentiation, hormone resistance
Received: October 15, 2016 Accepted: January 16, 2017 Published: January 27, 2017
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.
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