Tumor-associated macrophage (TAM)-derived CCL22 induces FAK addiction in esophageal squamous cell carcinoma (ESCC).
Tumor-associated macrophage (TAM)-derived CCL22 induces FAK addiction in esophageal squamous cell carcinoma (ESCC).
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DOI：
10.1038/s41423-022-00903-z
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发表时间：
2022-09
影响因子：
24.1
通讯作者：
Zhan, Qimin
中科院分区：
文献类型：
--
作者：
Chen, Jie;Zhao, Di;Zhang, Lingyuan;Zhang, Jing;Xiao, Yuanfan;Wu, Qingnan;Wang, Yan;Zhan, Qimin
肿瘤细胞对激活的癌基因的依赖被认为是治疗的靶点，但致癌微环境介导的细胞对特定的致癌信号分子的依赖仍有待进一步确定。在这里，我们发现肿瘤相关巨噬细胞(TAMs)产生丰富的C-C基序趋化因子22(CCL22)，其在肿瘤间质中的表达与肿瘤内磷酸化焦点黏附激酶(PFAK Tyr397)的水平、肿瘤转移和患者生存时间呈正相关。在功能上，CCL22刺激的FAK过度激活与癌细胞恶性进展的增加有关。CCL22诱导的FAK成瘾表现为对FAK特异性抑制对肿瘤进展的持续抑制。在机制上，我们发现二酰基甘油激酶α(DGKCCKα)作为信号转接子连接CCL22受体C-C基序趋化因子受体4(CCR4)和粘着斑块，并促进CCL22诱导的粘着斑块/AKT通路的激活。CCL22/CCR4信号激活细胞内钙/磷脂酶C-γ1(PLC-γ1)轴，刺激酪氨酸残基(Tyr335)上DGKα的磷酸化，并促进DGKα转位到质膜上组装DGKα/FAK信号体，这在调节癌细胞对FAK抑制剂的敏感性方面发挥了关键作用。驱动的瘤内FAK成瘾的发现为利用促癌微环境达到显著的抗癌作用提供了机会。
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 Tyr397), 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 kinase α (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 Ca2+/phospholipase C-γ1 (PLC-γ1) axis to stimulate the phosphorylation of DGKα at a tyrosine residue (Tyr335) and promoted the translocation of DGKα to 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.
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影响因子：
8
作者：
Baldanzi, G.;Cutrupi, S.;Graziani, A.
通讯作者：
Graziani, A.
影响因子：
--
作者：
Hao NB;Lü MH;Fan YH;Cao YL;Zhang ZR;Yang SM
通讯作者：
Yang SM
影响因子：
3.3
作者：
Lu, Yufei;Guo, Leiming;Ding, Gaofeng
通讯作者：
Ding, Gaofeng
影响因子：
--
作者：
Hatogai K;Kitano S;Fujii S;Kojima T;Daiko H;Nomura S;Yoshino T;Ohtsu A;Takiguchi Y;Doi T;Ochiai A
通讯作者：
Ochiai A
影响因子：
50.3
作者：
Chen J;Yao Y;Gong C;Yu F;Su S;Chen J;Liu B;Deng H;Wang F;Lin L;Yao H;Su F;Anderson KS;Liu Q;Ewen ME;Yao X;Song E
通讯作者：
Song E