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  2. Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

  • Cell Rep. 2022 Apr 5;39(1):110595. doi: 10.1016/j.celrep.2022.110595.
Hyunho Han 1 Yan Wang 2 Josue Curto 2 Sreeharsha Gurrapu 2 Sara Laudato 3 Alekya Rumandla 4 Goutam Chakraborty 5 Xiaobo Wang 6 Hong Chen 3 Yan Jiang 3 Dhiraj Kumar 2 Emily G Caggiano 4 Monica Capogiri 3 Boyu Zhang 3 Yan Ji 3 Sankar N Maity 7 Min Hu 8 Shanshan Bai 8 Ana M Aparicio 7 Eleni Efstathiou 7 Christopher J Logothetis 7 Nicholas Navin 8 Nora M Navone 7 Yu Chen 9 Filippo G Giancotti 10
Affiliations

Affiliations

  • 1 Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
  • 2 Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
  • 3 Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA.
  • 4 Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; UT MDACC UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
  • 5 Cell Biology Program, MSKCC, New York, NY 10065, USA.
  • 6 Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; UT MDACC UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
  • 7 Department of GU Oncology, UT MDACC, Houston, TX 77054, USA.
  • 8 Department of Genetics, UT MDACC, Houston, TX 77054, USA.
  • 9 Human Oncology and Pathogenesis Program and Department of Medicine, MSKCC, New York, NY 10065, USA.
  • 10 Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; Herbert Irving Comprehensive Cancer Center and Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: [email protected].
Abstract

Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: Androgen Receptor (AR) pathway + prostate Cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.

Keywords

BMP-SMAD signaling; CP: Cancer; TP53; androgen receptor signaling; prostate cancer.

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