Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer
Autor: | Cory Abate-Shen, Clémentine Le Magnen, Min Zou, Antonina Mitrofanova, Andrea Califano, Nicolas Floc'h, Yanping Sun, Mark A. Rubin, Elahe A. Mostaghel, Sheida Hayati, Michael M. Shen, Roxanne Toivanen, Daniel Chester |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Male Biology Neuroendocrine tumors urologic and male genital diseases Neuroendocrine differentiation Article SOXC Transcription Factors 03 medical and health sciences Prostate cancer Mice Cell Line Tumor medicine PTEN Animals Humans Neurons Transdifferentiation PTEN Phosphohydrolase Prostatic Neoplasms Cancer 500 Science medicine.disease Gene Expression Regulation Neoplastic Disease Models Animal Neuroendocrine Tumors Prostatic Neoplasms Castration-Resistant 030104 developmental biology Treatment Outcome Oncology Drug Resistance Neoplasm Receptors Androgen Cell Transdifferentiation Immunology Cancer research biology.protein Adenocarcinoma 570 Life sciences biology Androstenes Tumor Suppressor Protein p53 Signal Transduction |
Zdroj: | Cancer discovery. 7(7) |
ISSN: | 2159-8290 |
Popis: | Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of Trp53 and Pten, which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation. Significance: Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens. Cancer Discov; 7(7); 736–49. ©2017 AACR. See related commentary by Sinha and Nelson, p. 673. This article is highlighted in the In This Issue feature, p. 653 |
Databáze: | OpenAIRE |
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