Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

被引：196

作者：

Chan, Joseph M. ^{[1
,2
]}

Zaidi, Samir ^{[3
,4
]}

Love, Jillian R. ^{[3
]}

Zhao, Jimmy L. ^{[3
]}

Setty, Manu ^{[2
]}

Wadosky, Kristine M. ^{[5
]}

Gopalan, Anuradha ^{[6
]}

Choo, Zi-Ning ^{[2
]}

Persad, Sitara ^{[2
,7
]}

Choi, Jungmin ^{[8
]}

LaClair, Justin ^{[3
]}

Lawrence, Kayla E. ^{[3
]}

Chaudhary, Ojasvi ^{[2
]}

Xu, Tianhao ^{[2
]}

Masilionis, Ignas ^{[2
]}

Linkov, Irina ^{[6
]}

Wang, Shangqian ^{[3
]}

Lee, Cindy ^{[3
]}

Barlas, Afsar ^{[9
]}

Morris, Michael J. ^{[4
]}

Mazutis, Linas ^{[2
,10
]}

Chaligne, Ronan ^{[2
]}

Chen, Yu ^{[3
]}

Goodrich, David W. ^{[5
]}

Karthaus, Wouter R. ^{[3
]}

Pe'er, Dana ^{[2
,11
]}

Sawyers, Charles L. ^{[3
,11
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Med, Thorac Oncol Serv, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Program Computat & Syst Biol, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Genitourinary Oncol, New York, NY 10065 USA

[5] Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[7] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA

[8] Korea Univ, Dept Biomed Sci, Coll Med, Seoul, South Korea

[9] Mem Sloan Kettering Canc Ctr, Mol Cytol Core Facil, New York, NY 10065 USA

[10] Vilnius Univ, Life Sci Ctr, Inst Biotechnol, Vilnius, Lithuania

[11] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA

来源：

SCIENCE | 2022年 / 377卷 / 6611期

关键词：

DIFFERENTIATION THERAPY; RESISTANCE; IDENTIFICATION; EVOLUTION; MELANOMA; CELLS;

D O I：

10.1126/science.abn0478

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

引用

页码：1180 / 1191

页数：12

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