Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma.
Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma.
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细胞外基质重塑激活跨膜受体酪氨酸激酶 DDR1-STAT3 级联促进葡萄膜黑色素瘤肝转移定植
DOI：
10.1038/s41392-021-00563-x
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发表时间：
2021-05-12
影响因子：
39.3
通讯作者：
Pan J
中科院分区：
文献类型：
--
作者：
Dai W;Liu S;Wang S;Zhao L;Yang X;Zhou J;Wang Y;Zhang J;Zhang P;Ding K;Li Y;Pan J
定植被认为是转移级联的限速步骤。然而，其基本机制还不清楚。葡萄膜黑色素瘤（UM）是一种以单器官肝转移为特征的恶性肿瘤，它可以为认识复杂的定植过程提供一个简化的模型。由于在UM细胞系和标本中鉴定到DDR 1过表达，并且在转移性UM患者的肝脏微环境中注意到细胞外基质胶原（一种DDR 1配体）的丰富病理性沉积，因此我们假设DDR 1及其配体可能引发UM细胞与其周围肝脏小生境之间的相互作用，从而赋予增强的存活、增殖，并最终促进肝脏中的转移性定殖。我们测试了这一假设，发现DDR 1促进了这些恶性细胞表型，并促进了UM在肝脏中的转移定植。从机制上讲，UM细胞分泌TGF-β1，其诱导静止的肝星状细胞（qHSC）转化为分泌I型胶原的活化的HSC（aHSC）。细胞外基质的这种重塑反过来激活了DDR 1，通过上调STAT 3依赖性Mcl-1表达来增强存活，通过上调STAT 3依赖性SOX 2来增强干性，并促进癌细胞中的克隆形成。通过使用特异性抑制剂7 rh靶向DDR 1，抑制体外和体内生长的增殖和存活。更重要的是，通过药物灭活DDR 1靶向癌细胞或靶向微环境TGF-β1-胶原I环在小鼠中表现出显著的抗转移作用。总之，靶向DDR 1信号和TGF-β信号可能是减少UM肝转移的新方法。
Colonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.
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影响因子：
2.9
作者：
Lu, Qiu-Ping;Chen, Wen-Dan;Guan, Zhong
通讯作者：
Guan, Zhong
影响因子：
3.7
作者：
Modugno, Michele;Banfi, Patrizia;Galvani, Arturo
通讯作者：
Galvani, Arturo
影响因子：
13.5
作者：
García-Trevijano, ER;Iraburu, MJ;Rojkind, M
通讯作者：
Rojkind, M
影响因子：
7.3
作者：
Gao, Mingshan;Duan, Lei;Ding, Ke
通讯作者：
Ding, Ke
影响因子：
3.1
作者：
Fabregat, Isabel;Fernando, Joan;Sancho, Patricia
通讯作者：
Sancho, Patricia