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

doi:10.1016/j.celrep.2022.110595

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 EfstathiouChristopher J. Logothetis, Nicholas Navin, Nora M. Navone, Yu Chen, Filippo G. Giancotti

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English (US)
Article number	110595
Journal	Cell Reports
Volume	39
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2022.110595
State	Published - Apr 5 2022

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Research Animal Support Facility
Tissue Biospecimen and Pathology Resource
Functional Proteomics Reverse Phase Protein Array Core
SINGLE Core
Bioinformatics Shared Resource
Small Animal Imaging Facility

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10.1016/j.celrep.2022.110595

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Han, H., Wang, Y., Curto, J., Gurrapu, S., Laudato, S., Rumandla, A., Chakraborty, G., Wang, X., Chen, H., Jiang, Y., Kumar, D., Caggiano, E. G., Capogiri, M., Zhang, B., Ji, Y., Maity, S. N., Hu, M., Bai, S., Aparicio, A. M., ... Giancotti, F. G. (2022). Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis. Cell Reports, 39(1), Article 110595. https://doi.org/10.1016/j.celrep.2022.110595

Han, H, Wang, Y, Curto, J, Gurrapu, S, Laudato, S, Rumandla, A, Chakraborty, G, Wang, X, Chen, H , Jiang, Y, Kumar, D, Caggiano, EG, Capogiri, M, Zhang, B, Ji, Y, Maity, SN, Hu, M, Bai, S , Aparicio, AM, Efstathiou, E, Logothetis, CJ , Navin, N, Navone, NM, Chen, Y & Giancotti, FG 2022, 'Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis', Cell Reports, vol. 39, no. 1, 110595. https://doi.org/10.1016/j.celrep.2022.110595

@article{2c7df2a946184797871d24f39ccb1dc2,

title = "Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis",

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",

author = "Hyunho Han and Yan Wang and Josue Curto and Sreeharsha Gurrapu and Sara Laudato and Alekya Rumandla and Goutam Chakraborty and Xiaobo Wang and Hong Chen and Yan Jiang and Dhiraj Kumar and Caggiano, {Emily G.} and Monica Capogiri and Boyu Zhang and Yan Ji and Maity, {Sankar N.} and Min Hu and Shanshan Bai and Aparicio, {Ana M.} and Eleni Efstathiou and Logothetis, {Christopher J.} and Nicholas Navin and Navone, {Nora M.} and Yu Chen and Giancotti, {Filippo G.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = apr,

day = "5",

doi = "10.1016/j.celrep.2022.110595",

language = "English (US)",

volume = "39",

journal = "Cell Reports",

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T1 - Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis

AU - Han, Hyunho

AU - Wang, Yan

AU - Curto, Josue

AU - Gurrapu, Sreeharsha

AU - Laudato, Sara

AU - Rumandla, Alekya

AU - Chakraborty, Goutam

AU - Wang, Xiaobo

AU - Chen, Hong

AU - Jiang, Yan

AU - Kumar, Dhiraj

AU - Caggiano, Emily G.

AU - Capogiri, Monica

AU - Zhang, Boyu

AU - Ji, Yan

AU - Maity, Sankar N.

AU - Hu, Min

AU - Bai, Shanshan

AU - Aparicio, Ana M.

AU - Efstathiou, Eleni

AU - Logothetis, Christopher J.

AU - Navin, Nicholas

AU - Navone, Nora M.

AU - Chen, Yu

AU - Giancotti, Filippo G.

PY - 2022/4/5

Y1 - 2022/4/5

N2 - 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.

AB - 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.

KW - BMP-SMAD signaling

KW - CP: Cancer

KW - TP53

KW - androgen receptor signaling

KW - prostate cancer

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DO - 10.1016/j.celrep.2022.110595

M3 - Article

C2 - 35385726

AN - SCOPUS:85127487401

SN - 2211-1247

VL - 39

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 110595

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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