AKT2^(S128)/CCTα^(S315/319/323)-positive cancer-associated fibroblasts (CAFs) mediate focal adhesion kinase (FAK) inhibitors resistance via secreting phosphatidylcholines (PCs)  

作　　者：Jie Chen Lingyuan Zhang Yuheng Zhu Di Zhao Jing Zhang Yanmeng Zhu Jingyuan Pang Yuanfan Xiao Qingnan Wu Yan Wang Qimin Zhan 

机构地区：[1]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Laboratory of Molecular Oncology,Peking University Cancer Hospital&Institute,100142 Beijing,China [2]Peking University International Cancer Institute,Peking University,100191 Beijing,China [3]Research Unit of Molecular Cancer Research,Chinese Academy of Medical Sciences,Beijing,China [4]Soochow University Cancer Institute,Suzhou 215000,China [5]Institute of Cancer Research,Shenzhen Bay Laboratory,Shenzhen 518107,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第2期782-796,共15页信号转导与靶向治疗（英文）

基　　金：supported by the National Natural Science Foundation of China(81988101,81830086,and 81972243);CAMS Innovation Fund for Medical Sciences(2019-I2M-5-081);Suzhou Top-Notch Talent Groups(ZXD2022003);Major Program of Shenzhen Bay Laboratory(S201101004);Guangdong Basic and Applied Basic Research Foundation(2019B030302012);the Fund of“San-ming”Project of Medicine in Shenzhen(No.SZSM201812088).

摘　　要：Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)treatment.Additionally,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs.Consequently,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC production.This activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK inhibition.Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient survival.Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients.In conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.

关 键 词：CAFs metabolism RESISTANCE 

分 类 号：R735.1[医药卫生—肿瘤]