Tumor-associated macrophage(TAM)-derived CCL22 induces FAK addiction in esophageal squamous cell carcinoma(ESCC)  

作　　者：Jie Chen Di Zhao Lingyuan Zhang Jing Zhang 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,Beijing,100142,China [2]Peking University International Cancer Institute,Peking University,Beijing,100191,China [3]Research Unit of Molecular Cancer Research,Chinese Academy of Medical Sciences,Beijing,China [4]Institute of Cancer Research,Shenzhen Bay Laboratory,Shenzhen,518107,China

出　　处：《Cellular & Molecular Immunology》2022年第9期1054-1066,共13页中国免疫学杂志（英文版）

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

摘　　要：Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined.Here,we showed that tumor-associated macrophages(TAMs)produced an abundance of C-C motif chemokine 22(CCL22),whose expression in the tumor stroma was positively associated with the level of intratumoral phospho-focal adhesion kinase(pFAK Tyr^(397)),tumor metastasis and reduced patient survival.Functionally,CCL22-stimulated hyperactivation of FAK was correlated with increased malignant progression of cancer cells.CCL22-induced addiction to FAK was demonstrated by the persistent suppression of tumor progression upon FAK-specific inhibition.Mechanistically,we identified that diacylglycerol kinaseα(DGKα)acted as a signaling adaptor to link the CCL22 receptor C-C motif chemokine receptor 4(CCR4)and FAK and promoted CCL22-induced activation of the FAK/AKT pathway.CCL22/CCR4 signaling activated the intracellular Ca^(2+)/phospholipase C-γ1(PLC-γ1)axis to stimulate the phosphorylation of DGKαat a tyrosine residue(Tyr^(335))and promoted the translocation of DGKαto the plasma membrane to assemble the DGKα/FAK signalosome,which critically contributed to regulating sensitivity to FAK inhibitors in cancer cells.The identification of TAM-driven intratumoral FAK addiction provides opportunities for utilizing the tumor-promoting microenvironment to achieve striking anticancer effects.

关 键 词：Tumor-associated macrophages Esophageal squamous cell carcinoma FAK Oncogene addiction 

分 类 号：R735.1[医药卫生—肿瘤]