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

被引：42

作者：

Han, Hyunho ^{[1
,4
]}

Wang, Yan ^{[1
,2
,3
]}

Curto, Josue ^{[1
,2
,3
]}

Gurrapu, Sreeharsha ^{[1
,2
,3
]}

Laudato, Sara ^{[1
,14
]}

Rumandla, Alekya ^{[1
,5
]}

Chakraborty, Goutam ^{[6
,11
,12
]}

Wang, Xiaobo ^{[1
,2
,3
,5
]}

Chen, Hong ^{[1
]}

Jiang, Yan ^{[1
]}

Kumar, Dhiraj ^{[1
,2
,3
]}

Caggiano, Emily G. ^{[1
,5
]}

Capogiri, Monica ^{[1
]}

Zhang, Boyu ^{[1
]}

Ji, Yan ^{[1
]}

Maity, Sankar N. ^{[7
]}

Hu, Min ^{[8
]}

Bai, Shanshan ^{[8
]}

Aparicio, Ana M. ^{[7
]}

Efstathiou, Eleni ^{[7
,13
]}

Logothetis, Christopher J. ^{[7
]}

Navin, Nicholas ^{[8
]}

Navone, Nora M. ^{[7
]}

Chen, Yu ^{[9
,10
]}

Giancotti, Filippo G. ^{[1
,2
,3
]}

机构：

[1] UT MDACC, Dept Canc Biol, Houston, TX 77054 USA

[2] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Vagelos Coll Phys & Surg, New York, NY 10032 USA

[3] Columbia Univ, Dept Genet & Dev, Vagelos Coll Phys & Surg, New York, NY 10032 USA

[4] Yonsei Univ, Urol Sci Inst, Dept Urol, Coll Med, Seoul 03722, South Korea

[5] UT MDACC UT Hlth Grad Sch Biomed Sci, Houston, TX 77030 USA

[6] MSKCC, Cell Biol Program, New York, NY 10065 USA

[7] UT MDACC, Dept GU Oncol, Houston, TX 77054 USA

[8] UT MDACC, Dept Genet, Houston, TX 77054 USA

[9] MSKCC, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[10] MSKCC, Dept Med, New York, NY 10065 USA

[11] Icahn Sch Med Mt Sinai, Dept Urol, Tisch Canc Inst, New York, NY 10029 USA

[12] Icahn Sch Med Mt Sinai, Ctr Excellence Prostate Canc, Tisch Canc Inst, New York, NY 10029 USA

[13] Houston Methodist Hosp, GU Med Oncol, Houston, TX 77030 USA

[14] Tolremo Therapeut AC, Muttenz, Switzerland

来源：

CELL REPORTS | 2022年 / 39卷 / 01期

关键词：

NF-KAPPA-B; CASTRATION-RESISTANT; ANTIANDROGEN RESISTANCE; TRANSCRIPTION FACTORS; INCREASED SURVIVAL; CELL; RECEPTOR; BREAST; PROGRESSION; HETEROGENEITY;

D O I：

10.1016/j.celrep.2022.110595

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：34

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