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Principal Investigator: NINGLING KANG
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $358,744
Funding agency: National Cancer Institute
The development of liver metastasis is dependent upon bidirectional interactions between cancer cells and
the liver microenvironment. Transforming growth factor beta (TGFβ), released from cancer cells and other
resident liver cells, induces activation of hepatic stellate cells (HSCs) into myofibroblasts that in turn
promote liver metastasis. The long-term goal of our program is to define mechanisms governing HSC
activation and develop strategies to target HSCs and the prometastatic liver microenvironment. Recent
advances suggest that HSCs are fueled by aerobic glycolysis, glutaminolysis, and free cholesterol, but
mechanistic regulation of HSC metabolism is not fully defined. Glucose transporter 1 (Glut1) is a
predominant glucose transporter isoform expressed by hepatic fibroblasts and it has to be on the plasma
membrane for glucose to be transported into cells. Our Preliminary Data demonstrate that TGFβ1 induces
endosome-to-plasma-membrane translocation of Glut1 and glucose uptake into HSCs by a mechanism
dependent on non-receptor tyrosine kinase c-Src (Src) and vasodilator-stimulated phosphoprotein
(VASP). While Src interacts with the small Rab GTPase Rab11 and Glut1 at the endosome, VASP interacts
with Glut1 at the plasma membrane. Additionally, knockdown of Glut1 suppresses myofibroblastic activation of
HSCs in vitro and tumor-promoting effects of HSCs in a tumor/HSC co-implantation mouse model. These
findings led to the Central Hypothesis that the TGFβ1-induced localization of Glut1 on the plasma membrane
and the subsequent glucose transport into HSCs that fuels HSC activation are mediated by Src at the
endosome and VASP at the plasma membrane. In Aim 1, we will study how Src promotes Glut1 trafficking
towards the plasma membrane, with a focus on its regulation on Rab11 activation at the endosome. We will
also investigate how Src is activated in TGFβ1-stimulated HSCs. In Aim 2, we will elucidate how VASP retains
Glut1 at the plasma membrane and promotes glucose transport into HSCs. We will also interrogate whether a
lipid signaling pathway induces VASP phosphorylation in TGFβ1-stimulated HSCs. In Aim 3, we will use
conditional SLC2A1/Glut1 knockout mice and portal vein tumor injection to test if HSC-specific Glut1 deletion
suppresses HSC activation and colorectal liver metastasis in mice. We will also co-inject HSCs and tumor cells
into the livers of mice to test if the interplay between Src and VASP modulates plasma membrane Glut1,
glucose transport into HSCs, and HSC activation within the hepatic tumor microenvironment. The proposed
work will reveal novel mechanisms related to metabolic regulation of HSC activation induced by TGFβ, which
will help to identify new targets to inhibit HSC activation and the prometastatic liver microenvironment.
Terms: <Binding><Blood Plasma><Bone-Derived Transforming Growth Factor><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell membrane><Cells><Cellular Metabolic Process><Cellular biology><Cholesterol><Colon or Rectum><Colorectal><Cre-Lox><Cre-LoxP><Cre/LoxP><Cytoplasmic Membrane><D-Glucose><DNA Recombination><Data><Dextrose><EPH- and ELK-Related Tyrosine Kinase><EPH-and ELK-Related Kinase><Endosomes><Ephrin Type-A Receptor 8><Ephrin Type-A Receptor 8 Precursor><Erythrocyte/Hepatoma Glucose Transporter><Fibroblasts><GLUT><GLUT1><Generalized Growth><Genetic Recombination><Glucose><Glucose Binding Protein><Glucose Transport Protein><Glucose Transporter><Glucose Transporter 1><Goals><Growth><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Neoplasm Secondary><Hepatic Neoplasms><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatic metastasis><Hepatocyte><In Vitro><Injections><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Invaded><Isoforms><Ito Cell><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lipids><Liver><Liver Cells><Liver diseases><Liver neoplasms><Liver secondaries><Liver secondary cancer><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Metabolic><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Liver><Metastatic Tumor><Metastatic Tumor to the Liver><Metastatic malignant neoplasm to liver><Methods><Mice><Mice Mammals><Milk Growth Factor><Molecular Interaction><Murine><Mus><Myofibroblast><Neoplasm Metastasis><Null Mouse><Phosphorylation><Plasma><Plasma Membrane><Plasma Serum><Platelet Transforming Growth Factor><Portal Vein><Portal vein structure><Protein Isoforms><Protein Phosphorylation><Protein Tyrosine Kinase><Protein Tyrosine Kinase EEK><Proteins><Receptosomes><Recombination><Regulation><Reticuloendothelial System, Serum, Plasma><SLC2A1><SLC2A1 gene><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Solute Carrier Family 2, Facilitated Glucose Transporter, Member 1><Sphingolipids><TGF B><TGF-Beta 1><TGF-Beta1><TGF-beta><TGF-beta Receptors><TGF-β><TGF-β Receptors><TGFB><TGFB1><TGFB1 gene><TGFbeta><TGFβ><Testing><Tissue Growth><Transforming Growth Factor Beta 1><Transforming Growth Factor beta><Transforming Growth Factor beta Receptors><Transforming Growth Factor β Receptors><Transforming Growth Factor-Beta Family Gene><Tumor Cell><Tumor Promotion><Tumor-Derived><Tyrosine Kinase><Tyrosine-Protein Kinase Receptor EEK><Tyrosine-Specific Protein Kinase><Tyrosylprotein Kinase><VASP><Work><aerobic glycolysis><biological signal transduction><cancer cell><cancer imaging><cancer metastasis><cancer microenvironment><cell biology><cell metabolism><cellular metabaolism><colorectum><glucose transport><glucose uptake><hepatic body system><hepatic disease><hepatic neoplasia><hepatic neoplasm><hepatic organ system><hepatic tumor><hepatopathy><hydroxyaryl protein kinase><implantation><in vivo><interventional strategy><knock-down><knockdown><liver development><liver disorder><liver metastases><liver tumor><malignancy><malignant liver neoplasm, specified as secondary><metastasis in the liver><metastasis to the liver><metastasize to the liver><metastatic cancer to liver><metastatic liver><metastatic liver neoplasm><mouse model><murine model><neoplasm/cancer><neoplastic cell><novel><oncologic imaging><oncology imaging><ontogeny><plasmalemma><prevent><preventing><programs><rab G-Proteins><rab GTP-Binding Proteins><rab GTPases><response><secondary liver malignancy><secondary malignant liver neoplasm><trafficking><transforming growth factor beta1><tumor><tumor cell metastasis><tumor imaging><tumor microenvironment><tyrosyl protein kinase><vasodilator-stimulated phosphoprotein>