Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population.
Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population.
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基质SOX2上调通过产生SFRP1/2表达癌症相关的成纤维细胞种群来促进肿瘤发生。
DOI：
10.1016/j.devcel.2020.10.014
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发表时间：
2021-01-11
影响因子：
11.8
通讯作者：
Moscat J
中科院分区：
文献类型：
--
作者：
Kasashima H;Duran A;Martinez-Ordoñez A;Nakanishi Y;Kinoshita H;Linares JF;Reina-Campos M;Kudo Y;L'Hermitte A;Yashiro M;Ohira M;Bao F;Tauriello DVF;Batlle E;Diaz-Meco MT;Moscat J
癌症相关成纤维细胞（CAF）促进肿瘤恶性，但调节CAF表型获得的精确转录机制尚不清楚。我们发现，SOX 2的上调是这一过程的核心，这是由蛋白激酶C β（PKC β）抑制。PKC β缺乏激活结肠成纤维细胞的重编程以产生主要的SOX 2依赖性CAF群体，其表达WNT调节剂Sfrp 2作为其最高生物标志物。SOX 2直接结合Sfrp 1/2启动子，并且Sox 2或Sfrp 1/2在CAFs中的失活损害了结肠癌细胞的迁移和侵袭的诱导，以及它们在体内的致瘤性。重要的是，结直肠癌（CRC）患者的无复发和总生存率与基质PKC β水平呈负相关。此外，基质中的SOX 2表达与CRC T侵袭和无复发生存的预后较差相关。因此，PKC β-SOX 2轴成为控制CAF促肿瘤发生潜力的关键步骤。Kasashima等人描述了一种分子机制，其中基质中PKC z的缺失上调SOX 2以激活结肠成纤维细胞的重编程，从而产生表达SFRP 1/2的CAF群体。该人群支持上皮肿瘤进展，揭示了间充质CMS 4结直肠癌的脆弱性。
Cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. We show that the upregulation of SOX2 is central to this process, which is repressed by protein kinase Cζ (PKCζ). PKCζ deficiency activates the reprogramming of colonic fibroblasts to generate a predominant SOX2-dependent CAF population expressing the WNT regulator Sfrp2 as its top biomarker. SOX2 directly binds the Sfrp1/2 promoters, and the inactivation of Sox2 or Sfrp1/2 in CAFs impaired the induction of migration and invasion of colon cancer cells, as well as their tumorigenicity in vivo. Importantly, recurrence-free and overall survival of colorectal cancer (CRC) patients negatively correlates with stromal PKCζ levels. Also, SOX2 expression in the stroma is associated with CRC T invasion and worse prognosis of recurrence-free survival. Therefore, the PKCζ-SOX2 axis emerges as a critical step in the control of CAF pro-tumorigenic potential. Kasashima et al. describe a molecular mechanism whereby the loss of PKCz in the stroma upregulates SOX2 to activate the reprogramming of colonic fibroblasts generating a SFRP1/2-expressing CAF population. This population supports epithelial tumor progression, revealing vulnerabilities in mesenchymal CMS4 colorectal cancer.
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影响因子：
8.8
作者：
Llado V;Nakanishi Y;Duran A;Reina-Campos M;Shelton PM;Linares JF;Yajima T;Campos A;Aza-Blanc P;Leitges M;Diaz-Meco MT;Moscat J
通讯作者：
Moscat J
影响因子：
50.3
作者：
Jackstadt, Rene;van Hooff, Sander R.;Sansom, Owen J.
通讯作者：
Sansom, Owen J.
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
8
作者：
Kato M;Placencio-Hickok VR;Madhav A;Haldar S;Tripathi M;Billet S;Mishra R;Smith B;Rohena-Rivera K;Agarwal P;Duong F;Angara B;Hickok D;Liu Z;Bhowmick NA
通讯作者：
Bhowmick NA
DOI：
10.1042/bcj20160943
发表时间：
2017-04-24
期刊：
The Biochemical journal
影响因子：
--
作者：
Lakshmi SP;Reddy AT;Reddy RC
通讯作者：
Reddy RC