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3D matrix promotes cell dedifferentiation into colorectal cancer stem cells via integrin/cytoskeleton/glycolysis signaling
Cancer Science ( IF 5.7 ) Pub Date : 2022-09-02 , DOI: 10.1111/cas.15548
Tong Han 1 , Yuhong Jiang 1 , Xiaobo Wang 1 , Shuangya Deng 1 , Yongjun Hu 1 , Qianqian Jin 1 , Dongju Long 1 , Kuijie Liu 1
Affiliation  

The potential for tumor occurrence triggered by cancer stem cells (CSCs) has emerged as a significant challenge for human colorectal cancer therapy. However, the underlying mechanism of CSC development remains controversial. Our study provided evidence that the bulk of tumor cells could dedifferentiate to CSCs and reacquire CSC-like phenotypes if cultured in the presence of extracellular matrix reagents, such as Matrigel and fibrin gels. In these 3D gels, CD133 colorectal cancer cells can regain tumorigenic potential and stem-like phenotypes. Mechanistically, the 3D extracellular matrix could mediate cytoskeletal F-actin bundling through biomechanical force associated receptors integrin β1 (ITGB1), contributing to the release of E3 ligase tripartite motif protein 11 (TRIM11) from cytoskeleton and degradation of the glycolytic rate-limiting enzyme phosphofructokinase (PFK). Consequently, PFK inhibition resulted in enhanced glycolysis and upregulation of hypoxia-inducible factor 1 (HIF1α), thereby promoting the reprogramming of stem cell transcription factors and facilitating tumor progression in patients. This study provided novel insights into the role of the extracellular matrix in the regulation of CSC dedifferentiation in a cytoskeleton/glycolysis-dependent manner.

中文翻译:

3D 基质通过整合素/细胞骨架/糖酵解信号促进细胞去分化为结直肠癌干细胞

由癌症干细胞 (CSC) 引发的肿瘤发生潜力已成为人类结直肠癌治疗的重大挑战。然而,CSC发展的潜在机制仍然存在争议。我们的研究提供的证据表明,如果在细胞外基质试剂(例如 Matrigel 和纤维蛋白凝胶)的存在下培养,大部分肿瘤细胞可以去分化为 CSC 并重新获得 CSC 样表型。在这些 3D 凝胶中,CD133 -结直肠癌细胞可以恢复致瘤潜能和干细胞样表型。从机制上讲,3D 细胞外基质可以通过生物力学力相关受体整合素 β1 (ITGB1) 介导细胞骨架 F-肌动蛋白捆绑,有助于从细胞骨架释放 E3 连接酶三联基序蛋白 11 (TRIM11) 并降解糖酵解限速酶磷酸果糖激酶(PFK)。因此,PFK 抑制导致糖酵解增强和缺氧诱导因子 1 (HIF1α) 的上调,从而促进干细胞转录因子的重编程并促进患者的肿瘤进展。该研究为细胞外基质在以细胞骨架/糖酵解依赖性方式调节 CSC 去分化中的作用提供了新的见解。
更新日期:2022-09-02
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