肝星状细胞
原癌基因酪氨酸蛋白激酶Src
过剩1
转录组
转移
癌症研究
葡萄糖转运蛋白
化学
细胞生物学
生物
信号转导
内分泌学
癌症
基因表达
基因
生物化学
胰岛素
遗传学
作者
Yuanguo Wang,Xianghu Wang,Bing Bai,Aurpita Shaha,Xiang He,Yuqing He,Zhenqing Ye,Vijay H. Shah,Ningling Kang
标识
DOI:10.1097/hep.0000000000000763
摘要
Background and Aims: TGFβ1 induces hepatic stellate cell (HSC) activation into metastasis-promoting cancer-associated fibroblasts (CAFs), but how the process is fueled remains incompletely understood. We studied metabolic reprograming induced by TGFβ1 in HSCs. Approaches and Results: Activation of cultured primary human HSCs was assessed by expression of myofibroblast markers. Glucose transporter 1 (Glut1) of murine HSC was disrupted by Cre /LoxP recombination. Plasma membrane (PM) Glut1 and glycolysis were studied by biotinylation assay and the Angilent Seahorse XFe96 Analyzer. Subcutaneous HSC/tumor co-implantation and portal vein injection of MC38 colorectal cancer cells into HSC-specific Glut1 knockout mice were performed to determine in vivo relevance. Transcriptome was obtained by RNA sequencing of HSCs and spatialomics with MC38 liver metastases. TGFβ1-induced CAF activation of HSCs was accompanied by elevation of PM Glut1, glucose uptake, and glycolysis. Targeting Glut1 or Src by shRNA, pharmacologic inhibition, or a Src SH3 domain deletion mutant abrogated TGFβ1-stimulated PM accumulation of Glut1, glycolysis, and CAF activation. Mechanistically, binding of Src SH3 domain to SH3BP5 led to a Src/SH3BP5/Rab11/Glut1 complex that activated Rab11-dependent Glut1 PM transport under TGFβ1 stimulation. Deleting the Src SH3 domain or targeting Glut1 of HSCs by shRNA or Cre /LoxP recombination suppressed CAF activation in mice and MC38 colorectal liver metastasis. Multi-omics revealed that Glut1 deficiency in HSCs/CAFs suppressed HSC expression of tumor-promoting factors and altered MC38 transcriptome, contributing to reduced MC38 liver metastases. Conclusion: The Src SH3 domain-facilitated metabolic reprogramming induced by TGFβ1 represents a target to inhibit CAF activation and the pro-metastatic liver microenvironment.
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