Fibrinogen activates focal adhesion kinase (FAK) promoting colorectal adenocarcinoma growth.
Fibrinogen activates focal adhesion kinase (FAK) promoting colorectal adenocarcinoma growth.
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DOI：
10.1111/jth.15440
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Palumbo JS
中科院分区：
文献类型：
--
作者：
Sharma BK;Mureb D;Murab S;Rosenfeldt L;Francisco B;Cantrell R;Karns R;Romick-Rosendale L;Watanabe-Chailland M;Mast J;Flick MJ;Whitlock PW;Palumbo JS
We previously showed that fibrinogen is a major determinant of the growth of a murine model of colorectal cancer (CRC). Our aim was to define the mechanisms coupling fibrin(ogen) to CRC growth. CRC tumors transplanted into the dorsal subcutis of Fib− mice were less proliferative and demonstrated increased senescence relative to those grown in Fib+ mice. RNA-Seq analyses of Fib+ and Fib− tumors revealed 213 differentially regulated genes. One gene highly upregulated in tumors from Fib− mice was stratifin, encoding 14-3-3σ, a master regulator of proliferation/senescence. In a separate cohort, we observed significantly increased protein levels of 14-3-3σ and its upstream and downstream targets (i.e., p53 and p21) in tumors from Fib− mice. In vitro analyses demonstrated increased tumor cell proliferation in a fibrin printed 3D environment compared to controls, suggesting that fibrin(ogen) in the tumor microenvironment promotes tumor growth in this context via a tumor cell intrinsic mechanism. In vivo analyses showed diminished activation of focal adhesion kinase (FAK), a key negative regulator of p53, in Fib− tumors. Furthermore, NMR-based metabolomics demonstrated significantly reduced metabolic activity in tumors from Fib− relative to Fib+ mice. Together these findings suggest that fibrin(ogen)-mediated engagement of colon cancer cells activates FAK, which inhibits p53 and its downstream targets including 14-3-3σ and p21, thereby promoting cellular proliferation and preventing senescence. These studies suggest that fibrin(ogen) is an important component of the colon cancer microenvironment and may be exploited as a potential therapeutic target.
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