FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer

被引：89

作者：

Han, Ming ^{[1
,2
]}

Li, Feii ^{[1
,2
]}

Zhang, Yehan ^{[1
,2
]}

Dai, Pengfei ^{[1
,2
]}

He, Juan ^{[1
,2
]}

Li, Yunguang ^{[1
,2
]}

Zhu, Yiqin ^{[1
]}

Zheng, Junke ^{[3
]}

Huang, Hai ^{[4
]}

Bai, Fan ^{[5
]}

Gao, Dong ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Chinese China, Shanghai Key Lab Mol Androl,State Key Lab Cell Bio, Shanghai 200031, Peoples R China

[2] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Tongren Hosp, Hongqiao Int Inst Med, Fac Basic Med,Sch Med,Key Lab Cell Differentiat &, Shanghai 200025, Peoples R China

[4] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Urol, Guangzhou 510120, Peoples R China

[5] Peking Univ, Biomed Pioneering Innovat Ctr BIOPIC, Beijing Adv Innovat Ctr Genom ICG, Sch Life Sci, Beijing 100871, Peoples R China

来源：

CANCER CELL | 2022年 / 40卷 / 11期

基金：

中国国家自然科学基金;

关键词：

SMALL-CELL CARCINOMA; PHENOTYPE; RESISTANCE; PROGRESSION; ALIGNMENT; THERAPY; SEQ;

D O I：

10.1016/j.ccell.2022.10.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Prostate cancer adeno-to-neuroendocrine lineage transition has emerged as a mechanism of targeted ther-apeutic resistance. Identifying the direct molecular drivers and developing pharmacological strategies using clinical-grade inhibitors to overcome lineage transition-induced therapeutic resistance are imperative. Here, using single-cell multiomics analyses, we investigate the dynamics of cellular heterogeneity, transcriptome regulation, and microenvironmental factors in 107,201 cells from genetically engineered mouse prostate can-cer samples with complete time series of tumor evolution seen in patients. We identify that FOXA2 orches-trates prostate cancer adeno-to-neuroendocrine lineage transition and that Foxa2 expression is significantly induced by androgen deprivation. Moreover, Foxa2 knockdown induces the reversal of adeno-to-neuroen-docrine transition. The KIT pathway is directly regulated by FOXA2 and specifically activated in neuroendo-crine prostate cancer (NEPC). Pharmacologic inhibition of KIT pathway significantly suppresses mouse and human NEPC tumor growth. These findings reveal that FOXA2 drives adeno-to-neuroendocrine lineage plas-ticity in prostate cancer and provides a potential pharmacological strategy for castration-resistant NEPC.

引用

页码：1306 / +

页数：27

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