Activated Hgf-Met signaling cooperates with oncogenic Braf to drive primary cutaneous melanomas and angiotropic lung metastases in mice.
Activated Hgf-Met signaling cooperates with oncogenic Braf to drive primary cutaneous melanomas and angiotropic lung metastases in mice.
复制标题
激活的 Hgf-Met 信号传导与致癌 Braf 协同作用，驱动小鼠原发性皮肤黑色素瘤和血管性肺转移
DOI：
10.1016/j.jid.2019.12.020
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Gaffal E
中科院分区：
文献类型：
--
作者：
Braun AD;Mengoni M;Bonifatius S;Tüting T;Gaffal E
BRAF激酶基因的致癌突变是获得性黑色素细胞痣和皮肤黑色素瘤中最常见的基因组驱动因素。目前认为癌基因诱导的衰老和细胞周期阻滞限制了致癌BRAF促进良性痣中黑素细胞增殖的能力。致癌BRAF突变使黑素细胞完全转化为侵袭性生长的黑色素瘤细胞，并能全身转移的分子和细胞机制仅部分了解。在这项研究中，我们在遗传小鼠模型中显示，组成性增强的Hgf-Met信号转导与致癌BRAF合作，以驱动肿瘤的发展和转移扩散。在转基因Hg过表达和致癌CDK 4种系突变的小鼠中，致癌BRAF的激活加速并增加了原发性皮肤黑色素瘤的发展。原发性黑色素瘤表现出相当大的表型异质性，经常出现去分化的迹象。Hgf-CDK 4小鼠的BRAF激活也增加了肺转移的数量。黑色素瘤细胞在原发性肿瘤和肺转移灶的侵袭性前沿均表现出明显的血管生长模式。综上所述，我们的工作支持了激活的Hgf-Met信号传导和致癌BRAF在黑色素瘤发病机制中的协同作用。
Oncogenic mutations in theBRAFkinase gene represent the most frequent genomic driver in acquired melanocytic nevi and in cutaneous melanomas. It is currently thought that oncogene-induced senescence and cell cycle arrest limit the ability of oncogenicBRAFto promote melanocyte proliferation in benign nevi. The molecular and cellular mechanisms that allow an oncogenicBRAFmutation to fully transform melanocytes into invasively growing melanoma cells that are able to metastasize systemically are only partially understood. In this study, we show in a genetic mouse model that constitutively enhanced Hgf-Met signaling cooperates with oncogenicBRAFto drive tumor development and metastatic spread. Activation of oncogenicBRAFin mice with transgenicHgfoverexpression and an oncogenicCDK4germline mutation accelerated and increased the development of primary cutaneous melanomas. Primary melanomas showed considerable phenotypic heterogeneity with frequent signs of dedifferentiation.BRAFactivation inHgf-CDK4mice also increased the number of lung metastases. Melanoma cells showed a pronounced angiotropic growth pattern both at the invasive front in primary tumors and in metastatic lesions of the lung. Taken together, our work supports the notion that activated Hgf-Met signaling and oncogenicBRAFcan cooperate in melanoma pathogenesis.
登录
查看更多内容
影响因子：
32.4
作者：
Glodde, Nicole;Bald, Tobias;Hoelzel, Michael
通讯作者：
Hoelzel, Michael
影响因子：
11.2
作者：
D. Tormo;Aleix Ferrer;P. Bosch;E. Gaffal;E. Basner-Tschakarjan;J. Wenzel;T. Tüting
通讯作者：
D. Tormo;Aleix Ferrer;P. Bosch;E. Gaffal;E. Basner-Tschakarjan;J. Wenzel;T. Tüting
影响因子：
3.1
作者：
Pereira, Nigel;Reichman, David E.;Rosenwaks, Zev
通讯作者：
Rosenwaks, Zev
影响因子：
6
作者：
Hooijkaas, Anna I.;Gadiot, Jules;Blank, Christian U.
通讯作者：
Blank, Christian U.
影响因子：
64.8
作者：
Bald, Tobias;Quast, Thomas;Tueting, Thomas
通讯作者：
Tueting, Thomas