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Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer

文献类型：期刊论文

作者Cheng, Chaping9,10; Wang, Jinming9,10; Xu, Penghui9,10; Zhang, Kai9,10; Xin, Zhixiang9,10; Zhao, Huifang9,10; Ji, Zhongzhong9,10; Zhang, Man7,8; Wang, Deng7,8,9,10; He, Yuman9,10
刊名NATURE CANCER
出版日期2022-05-01
卷号3期号:5页码:565-+
DOI10.1038/s43018-022-00380-3
通讯作者Gao, Wei-Qiang(gao.weiqiang@sjtu.edu.cn) ; Zhu, Helen He(zhuhecrane@shsmu.edu.cn)
英文摘要Zhu and colleagues identify GREMLIN1 as an FGFR1 ligand that promotes plasticity and castration resistance in prostate cancer through regulation of MAPK signaling, and show that anti-GREMLIN1 antibody therapy synergizes with androgen deprivation. Among the greatest hurdles in clinical management of prostate cancer (PCa) are the progression to lethal castration-resistant prostate cancer (CRPC) and the lack of suitable targeted therapies for advanced disease. Here we identify Gremlin1 as a ligand for fibroblast growth factor receptor 1 (FGFR1), which promotes lineage plasticity and drives castration resistance. Importantly, we generate a specific anti-Gremlin1 therapeutic antibody and demonstrate synergistic effect with androgen deprivation therapy (ADT) in CRPC. GREM1 transcription is suppressed by androgen receptor (AR) and released following ADT. We show that Gremlin1 binds to FGFR1 and activates downstream MAPK signaling. Gremlin1 interacts with FGFR1 differently to its canonical ligand FGF1, as revealed through protein structure docking and mutagenesis experiments. Altogether, our data indicate Gremlin1 as a promising candidate therapeutic target for CRPC.
WOS关键词STEM-CELL ; ACTIVATING MUTATIONS ; ANTIANDROGEN ; BONE ; UBIQUITINATION ; RECEPTORS ; REVEALS ; PROMOTE ; PROTEIN
资助项目National Key R&D Program of China[2017YFA0102900] ; National Natural Science Foundation of China[NSFC32022021] ; National Natural Science Foundation of China[NSFC81972404] ; Program of Shanghai Academic/Technology Research Leader[21XD1422300] ; Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support[20181706] ; Innovative research team of high-level local universities in Shanghai ; NSFC[81630073] ; NSFC[81872406] ; 111project[B21024] ; Science and Technology Commission of Shanghai Municipality[20JC1417600] ; Science and Technology Commission of Shanghai Municipality[21JC1404100] ; Peak Disciplines (Type VI) of Institutes of Higher Learning in Shanghai ; Shanghai Jiao Tong University STAR and Scientific and Technological Innovation Funds ; KC Wong foundation ; Mabspace Biosciences
WOS研究方向Oncology
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000800792900006
源URL[http://119.78.100.183/handle/2S10ELR8/301310]  
专题新药研究国家重点实验室
通讯作者Gao, Wei-Qiang; Zhu, Helen He
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
3.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou, Peoples R China
4.Zhengzhou Univ, Chinese Minist Educ, Key Lab Cell Differentiat & Apoptosis, Zhengzhou, Peoples R China
5.Mabspace Biosci Suzhou Co Ltd, Suzhou, Peoples R China
6.Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Cell Biol,Shanghai Key Lab Mol Andr, Shanghai, Peoples R China
7.Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai, Peoples R China
8.Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai, Peoples R China
9.Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, Dept Urol, Shanghai, Peoples R China
10.Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med,State Key Lab Oncogenes & Related Genes, Renji Med X Stem Cell Res Ctr,Shanghai Canc Inst, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Cheng, Chaping,Wang, Jinming,Xu, Penghui,et al. Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer[J]. NATURE CANCER,2022,3(5):565-+.
APA Cheng, Chaping.,Wang, Jinming.,Xu, Penghui.,Zhang, Kai.,Xin, Zhixiang.,...&Zhu, Helen He.(2022).Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer.NATURE CANCER,3(5),565-+.
MLA Cheng, Chaping,et al."Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer".NATURE CANCER 3.5(2022):565-+.

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来源：上海药物研究所

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