p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis.
p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis.
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DOI：
10.1101/gad.290346.116
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发表时间：
2016-12-01
影响因子：
10.5
通讯作者：
Bulavin DV
中科院分区：
文献类型：
--
作者：
Brichkina A;Bertero T;Loh HM;Nguyen NT;Emelyanov A;Rigade S;Ilie M;Hofman P;Gaggioli C;Bulavin DV
Brichkina等人表明，肺癌生长取决于癌症小生境产生的短距离线索，并在p38驱动的肿瘤发生中心鉴定成纤维细胞特异性透明质酸合成。这反过来又调节早期基质成纤维细胞活化，转化为癌相关成纤维细胞（CAF）和癌细胞增殖。肿瘤性病变的扩展产生了引发肿瘤小生境形成的初始信号。微环境中的非转化细胞类型不断与肿瘤细胞共同进化以促进肿瘤发生。在这里，我们确定p38 MAPK作为人类肺癌的关键组成部分，特别是间质相互作用，它提供了一个早期的，protumorigenic信号在组织微环境。我们发现，肺癌的生长依赖于癌症小生境以p38依赖的方式产生的短距离线索。我们确定了成纤维细胞特异性透明质酸合成的中心p38驱动的肿瘤发生，调节早期基质成纤维细胞活化，转化为癌相关的成纤维细胞（CAF），和癌细胞增殖。系统下调p38 MAPK信号转导在敲入模型与激活Tyr 182取代苯丙氨酸或条件性消融p38在成纤维细胞中具有显着的肿瘤抑制作用的K-ras肺肿瘤的发生。此外，Kras驱动的小鼠肺肿瘤和原位生长的原发性人肺癌都显示出对化学p38抑制剂和透明质酸合成的非处方抑制剂的显著敏感性。我们认为肿瘤微环境的p38 MAPK-透明质酸依赖性重编程在驱动肺肿瘤发生中起着关键作用，而阻断这一过程可能具有深远的治疗意义。
Brichkina et al. show that lung cancer growth depends on short-distance cues produced by the cancer niche and identify fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis. This in turn regulates early stromal fibroblast activation, the conversion to carcinoma-associated fibroblasts (CAFs), and cancer cell proliferation. Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner. We identified fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to carcinoma-associated fibroblasts (CAFs), and cancer cell proliferation. Systemic down-regulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38 in fibroblasts has a significant tumor-suppressive effect on K-ras lung tumorigenesis. Furthermore, both Kras-driven mouse lung tumors and orthotopically grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that p38MAPK–hyaluronan-dependent reprogramming of the tumor microenvironment plays a critical role in driving lung tumorigenesis, while blocking this process could have far-reaching therapeutic implications.
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影响因子：
10.5
作者：
Brancho, D;Tanaka, N;Davis, RJ
通讯作者：
Davis, RJ
DOI：
10.1165/ajrcmb.26.5.4689
发表时间：
2002-05-01
影响因子：
6.4
作者：
Greenberg, AK;Basu, S;Lee, TC
通讯作者：
Lee, TC
影响因子：
30.8
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
通讯作者：
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影响因子：
3.7
作者：
Kultti, Anne;Pasonen-Seppanen, Sanna;Tammi, Markku I.
通讯作者：
Tammi, Markku I.
影响因子：
4.8
作者：
Kakizaki, I;Kojima, K;Itano, N
通讯作者：
Itano, N