Robert F. Schwabe, MD
The aim of the Schwabe lab is to understand the regulation of wound healing responses to chronic liver injury with a specific focus on how the activation of hepatic stellate cells promotes liver fibrosis and liver carcinogenesis. We postulate that many pathways that promote beneficial wound healing responses in the short term, promote the development of fibrosis and cancer in the long term.
1. Inflammation and wound healing: Inflammation is a characteristic feature of chronic liver injury. Despite the overwhelming association between inflammation and wound healing in virtually all stages of liver injury, the causal contribution of inflammation towards the development of liver fibrosis and cancer is not well understood. Our laboratory hypothesizes that there is an increased exposure of the liver to inflammatory mediators released from the intestinal microbiota, and that these products trigger inflammatory signaling cascades that promote the development of liver cancer and fibrosis. The laboratory is focusing on the involvement of the gut microbiota, Toll-like receptors and their downstream mediators such as NF-kB and JNK in the promotion of fibrogenesis and carcinogenesis.
2. Characterization of stellate cell activation: Following liver injury, stellate cells undergo a phenotypic change to transform from vitamin A storing, lipid droplet-containing cells to myofibroblast-like cells. However, this transformation has been largely studied in cell culture, and the role of stellate cells as predominant source of liver myofibroblasts in the fibrotic liver has not been established without absolute certainty. Using a novel "snapshot" technology that allows to purify stellate cells from the fibrotic liver without any plating or other artifacts, the Schwabe lab is characterizing in detail cellular programs that regulate stellate cell activation, and is modulating these pathways in a stellate cell-specific manner to determine the relevance of key pathway in vivo.
3. Endocannabinoids and liver disease: Endocannabinoids are bioactive lipids that regulate a wide range of biological functions such as food intake, metabolism, inflammation, cell proliferation and apoptosis. The Schwabe lab is interested how endocannbinoids affect wound healing responses in different cellular compartments of the liver. Using genetic approaches, the lab is studying how cell-specific inactivation of cannabinoid receptors or increases in endocannabinoid levels affect wound healing response to chronic injury.
4. Generation of novel mouse models of liver fibrosis, inflammation and cancer: The Schwabe lab is using Bac recombineering technology to generate a number of novel genetic models of liver fibrosis, inflammation and hepatocellular cancer. The approaches includes the (i) generation of novel Cre transgenic lines, (ii) floxing of target genes and (iii) the generation of "knock-in" mice with point mutations in specific pathways.
My research seeks to elucidate mechanisms by which fibrosis and cancer develop in the chronically injured liver using mouse models, patient samples as well as novel Systems Biology approaches. To understand the contribution of liver fibroblasts and the underlying pathways, my lab has generated hepatic stellate cell-selective Cre transgenic mouse (LratCre), allowing to trace and functionally manipulate hepatic stellate cell (HSC)-derived fibroblasts. Current efforts are to delineate the contribution of HSC to different types of injury and fibrosis, including non-alcoholic steatohepatitis (NASH), with the ultimate goal to identify novel druggable pathways that promote HSC activation and liver fibrosis. Besides fibrosis, my lab also investigates liver cancer development. Liver cancer is the second leading cause of cancer mortality world- wide, and almost never develops in healthy livers. In most patients, liver cancer develops after decades of chronic liver injury, inflammation and fibrosis, supporting the notion that liver cancer is “a wound that does not heal”. One interest of my laboratory is to unravel the relationship between fibrosis and cancer development. Using mouse models, we try to understand whether fibroblasts and ECM promote the development of hepatocellular carcinoma (HCC) using LratCre mice to ablate or functionally manipulate cancer-associated fibroblasts (CAF) in liver carcinogenesis. In addition, my laboratory is interested in the role of fibrosis and CAF in the development of cholangiocarcinoma (CCA). Using above-described tools such as LratCre-transgenic mice, we seek to uncover how the absence or inactivation of stellate cell-derived CAF and ECM proteins affects CCA development. Key data are confirmed using bulk and single cell RNA-sequencing as well as novel Systems Biology approaches in patient samples. Finally, my lab seeks to uncover druggable "master regulators" in HCC and CCA using novel Systems Biology approaches in collaboration with the Califano lab.
Filliol A, Schwabe RF. FoxM1 induces CCl2 secretion from hepatocytes triggering hepatic inflammation, injury, fibrosis, and liver cancer. Cell Mol Gastroenterol Hepatol. 2020; 9(3):555-556. PMID: 32008983
Hernandez C, Huebener P, Pradere JP, Antoine DJ, Friedman RA, Schwabe RF. HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis. J Clin Invest. 2018; 128(6):2436-2451. PMID: 29558367
Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017; 14(9):527-539. PMID: 28676707