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Principal Investigator: Robert F. Schwabe
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $481,473
Funding agency: National Cancer Institute
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, causing over 700,000
deaths annually. In the US, HCC rates have tripled in the last three decades. The rise in obesity, non-alcoholic
fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasingly contributing to advanced
liver disease and HCC development. Chronic injury, inflammation and fibrosis are strongly associated with
disease progression and HCC development in patients and sufficient to trigger HCC in mice - suggesting that
HCC truly represents “a wound that does not heal”. Even though HCC may develop in the absence of overt
cirrhosis in NASH, almost all NASH-HCCs still develop in fibrotic livers. Hence, fibrosis is one of the most
prominent but least understood risk factors for HCC and NASH-HCC. Moreover, fibrosis is a main determinant
of outcomes and most therapeutic efforts in NASH aim to reducing fibrosis. Hence, understanding the role of
fibroblasts in HCC development in NASH is highly relevant. We and others have previously shown that hepatic
stellate cells (HSC) are the main source of fibroblasts in the liver. This proposal is based on preliminary data
showing for the first time by reliable and complementary genetic approaches a strong promotion of HCC
development by HSC. However, while the overall effect of HSC in chronic liver disease is tumor-promoting, we
made the striking observation that HSC can both promote and protect from HCC. Based on this, our central
hypothesis is that a cytokine- and growth-factor secreting subpopulation (cyHSC), resembling quiescent HSC in
the healthy liver, protect from NASH-HCC whereas highly activated myfibroblastic HSC (myHSC) promote
NASH-HCC. Linked to this, we also propose the higher percentage of cyHSC in normal liver provide protections
from HCC in the healthy state, whereas the higher percent of myHSC in injured livers contribute to disease-
associated promotion of HCC. Here, we seek to functionally characterize the contribution of HSC-derived
fibroblasts and subpopulation-specific mediators in NASH-associated HCC. We will first determine the role of
HSC-derived fibroblasts by genetic depletion and inhibition approaches, and characterize HSC subpopulations
and their cellular and ligand-receptor interactions and their evolution during disease progression by single cell
RNA-sequencing and CellPhoneDB in murine and human NASH (Aim 1). We will determine the role of myHSC-
secreted mediators, focusing on type I collagen, its receptors and downstream pathways (Aim 2) as well as the
role of cyHSC-secreted mediators, focusing on hepatocyte growth factor and CXCL12 (Aim 3), in NASH-
associated HCC. Together, the proposed studies will reveal novel insights into the pathophysiology of NASH-
HCC and provide evidence for tumor-promoting as well as tumor-suppressive functions of HSC. These studies
may not only open up new therapeutic avenues, targeting tumor-promoting pathways while sparing or restoring
tumor-suppressive pathways, but also shift current paradigms on the role of HSC in HCC development.
Terms: <Ablation><Affect><CXCL12><CXCL12 gene><CXCL12 protein><Cancer Cause><Cancer Etiology><Cancers><Cell Communication and Signaling><Cell Count><Cell Number><Cell Signaling><Cell secretion><Cell-Extracellular Matrix><Cellular Secretion><Cessation of life><Chemokine (C-X-C Motif) Ligand 12><Cholangiocarcinoma><Cholangiocellular Carcinoma><Chronic><Cirrhosis><Collagen Receptors><Collagen Type I><Data><Death><Development><Disease><Disease Progression><Disorder><Dysfunction><ECM><Environment><Evolution><Extracellular Matrix><Fibroblasts><Fibrosis><Functional disorder><Genetic><Goals><Growth Agents><Growth Factor><Growth Substances><HGF gene><HGF/SF><Hepatic><Hepatic Cancer><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatocarcinogenesis><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatocyte Growth Factor><Hepatoma><Hepatopoietin A><Human><Immunity><Incidence><Inflammation><Injury><Injury to Liver><Intracellular Communication and Signaling><Ito Cell><Ligands><Link><Liver><Liver Carcinogenesis><Liver Cells><Liver Cells Carcinoma><Liver Fibrosis><Liver diseases><Lung Fibroblast-Derived Mitogen><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of liver><Malignant neoplasm of pancreas><Mediating><Mediator><Mice><Mice Mammals><Modern Man><Murine><Mus><Myofibroblast><NAFLD><NASH><Obesity><Outcome><PBSF><Pancreas Cancer><Pancreatic Cancer><Pathway interactions><Patients><Physiopathology><Pre-B Cell Growth Stimulating Factor><Prevention><Primary carcinoma of the liver cells><Production><Proteins Growth Factors><Receptor Protein><Regulation><Risk><Risk Factors><Role><SCYB12><SDF-1><SDF-1A><SDF-1B><SDF-1alpha><SDF1><SDF1A><SDF1B><Scatter Factor><Sdf1 protein><Signal Transduction><Signal Transduction Systems><Signaling><Source><Stromal Cell-Derived Factor 1><TLSF-A><TLSF-B><TPAR1><Therapeutic><Therapeutically Targetable><Time><Tumor Promotion><Type 1 Collagen><adiposity><biliary cancer><biological signal transduction><cancer microenvironment><carcinogenesis in the liver><cell type><cholangiosarcoma><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><chronic liver injury><cirrhotic><corpulence><cytokine><developmental><fatty liver disease><fibrotic liver><genetic approach><genetic strategy><hIRH><hepatic body system><hepatic carcinogenesis><hepatic cell proliferation><hepatic cellular proliferation><hepatic damage><hepatic disease><hepatic fibrosis><hepatic injury><hepatic organ system><hepatocellular carcinogenesis><hepatocyte cell proliferation><hepatocyte cellular proliferation><hepatocyte proliferation><hepatopathy><improved><injuries><insight><liver cancer><liver cancer pathogenesis><liver carcinoma><liver cell proliferation><liver cellular proliferation><liver damage><liver disorder><liver injury><liver malignancy><liver tumorigenesis><malignancy><malignant liver tumor><mortality><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-alcohol fatty liver disease><non-alcohol induced steatohepatitis><non-alcoholic fatty liver disease><non-alcoholic liver disease><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcoholic fatty liver disease><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pancreatic malignancy><pathophysiology><pathway><precancer><precancerous><premalignant><protection pathway><protective pathway><receptor><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stromal cell-derived factor-1alpha><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tissue wound><tumor><tumor microenvironment><viral liver disease><wound><wounding><wounds>