Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis
Hyunho Han,
Yan Wang,
Josue Curto,
Sreeharsha Gurrapu,
Sara Laudato,
Alekya Rumandla,
Goutam Chakraborty,
Xiaobo Wang,
Hong Chen,
Yan Jiang,
Dhiraj Kumar,
Emily G. Caggiano,
Monica Capogiri,
Boyu Zhang,
Yan Ji,
Sankar N. Maity,
Min Hu,
Shanshan Bai,
Ana M. Aparicio,
Eleni Efstathiou,
Christopher J. Logothetis,
Nicholas Navin,
Nora M. Navone,
Yu Chen,
Filippo G. Giancotti
Affiliations
Hyunho Han
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
Yan Wang
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
Josue Curto
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
Sreeharsha Gurrapu
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
Sara Laudato
Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
Alekya Rumandla
Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; UT MDACC UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA
Goutam Chakraborty
Cell Biology Program, MSKCC, New York, NY 10065, USA
Xiaobo Wang
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
Hong Chen
Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
Yan Jiang
Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
Dhiraj Kumar
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
Emily G. Caggiano
Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA; UT MDACC UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA
Monica Capogiri
Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
Boyu Zhang
Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
Yan Ji
Department of Cancer Biology, UT MDACC, Houston, TX 77054, USA
Sankar N. Maity
Department of GU Oncology, UT MDACC, Houston, TX 77054, USA
Min Hu
Department of Genetics, UT MDACC, Houston, TX 77054, USA
Shanshan Bai
Department of Genetics, UT MDACC, Houston, TX 77054, USA
Ana M. Aparicio
Department of GU Oncology, UT MDACC, Houston, TX 77054, USA
Eleni Efstathiou
Department of GU Oncology, UT MDACC, Houston, TX 77054, USA
Christopher J. Logothetis
Department of GU Oncology, UT MDACC, Houston, TX 77054, USA
Nicholas Navin
Department of Genetics, UT MDACC, Houston, TX 77054, USA
Nora M. Navone
Department of GU Oncology, UT MDACC, Houston, TX 77054, USA
Yu Chen
Human Oncology and Pathogenesis Program and Department of Medicine, MSKCC, New York, NY 10065, USA
Filippo G. Giancotti
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; Corresponding author
Summary: 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.
