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
  • 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].
PMID: 35385726 DOI: 10.1016/j.celrep.2022.110595
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.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-32721
    Neratinib
    99.94%, HER2/EGFR Inhibitor
    target: EGFR
    Research Areas: Cancer