Targeting Src SH3 domain-mediated glycolysis of HSC suppresses transcriptome, myofibroblastic activation, and colorectal liver metastasis.

Autor:	Wang Y; Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, Austin, Minnesota, USA., Wang X; Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, Austin, Minnesota, USA.; The School of Medicine, Taizhou University, Taizhou, Zhejiang, China., Bai B; Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, Austin, Minnesota, USA., Shaha A; Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, Austin, Minnesota, USA., He X; Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, Austin, Minnesota, USA.; The School of Chemistry and Chemical Engineering, Nanning, Guangxi, China., He Y; Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, Austin, Minnesota, USA.; The School of Environmental and Life Sciences, Nanning Normal University, Nanning, Guangxi, China., Ye Z; Department of Population Health Science, University of Texas Health San Antonio, San Antonio, Texas, USA., Shah VH; GI Research Unit and Cancer Cell Biology Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Kang N; Tumor Microenvironment and Metastasis, the Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
Jazyk:	angličtina
Zdroj:	Hepatology (Baltimore, Md.) [Hepatology] 2024 Sep 01; Vol. 80 (3), pp. 578-594. Date of Electronic Publication: 2024 Jan 24.
DOI:	10.1097/HEP.0000000000000763
Abstrakt:	Background and Aims: Transforming growth factor-beta 1 (TGFβ1) induces HSC activation into metastasis-promoting cancer-associated fibroblasts (CAFs), but how the process is fueled remains incompletely understood. We studied metabolic reprogramming induced by TGFβ1 in HSCs. Approaches and Results: Activation of cultured primary human HSCs was assessed by the expression of myofibroblast markers. Glucose transporter 1 (Glut1) of murine HSC was disrupted by Cre recombinase/LoxP sequence derived from bacteriophage P1 recombination (Cre/LoxP). Plasma membrane (PM) Glut1 and glycolysis were studied by biotinylation assay and the Angilent Seahorse XFe96 Analyzer. S.c. 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 short hairpin RNA, pharmacologic inhibition, or a Src SH3 domain deletion mutant abrogated TGFβ1-stimulated PM accumulation of Glut1, glycolysis, and CAF activation. Mechanistically, binding of the Src SH3 domain to SH3 domain-binding protein 5 led to a Src/SH3 domain-binding protein 5/Rab11/Glut1 complex that activated Rab11-dependent Glut1 PM transport under TGFβ1 stimulation. Deleting the Src SH3 domain or targeting Glut1 of HSCs by short hairpin RNA or Cre recombinase/LoxP sequence derived from bacteriophage P1 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. (Copyright © 2024 American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
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