This rapidly evolving area has become a main focus of the Schwabe lab. We are using single cell RNA-seq and spatial transciptomics data to understand mechanisms of cell-cell comunication and transcriptional regulation in health and disease. Our main focus lies in analyzing liver fibrosis, non-alcoholic fatty liver disease and hepatocellular carcinoma in patients - as these approaches for the first time allow a deep understanding of the underlying biology and pathobiology. We are combining analyses of transcriptional master regulators and cell-cell interactions by ARACNe, VIPER and CellPhoneDB in patients with genetic forward screens and state-of-the-art mouse models.
Our lab has made key contributions for the understanding of hepatic stellate cell (HSC) functions. We have developed transgenic mice (LratCre) that efficiently label and delete in HSC and demonstrated that HSC are the key contributors to the myofibroblast pool and liver fibrosis (Mederacke et al, Nat Comm 2013); that they can revert to a nearly quiescent state (Troger et al, Gastroenterology 2012); that they promote desmoplastic tumor growth (Affo et al, Cancer Cell 2021; Bhattacharjee et al, J Clin Invest 2021); and have established highly efficient and pure isolation protocols (Mederacke et al, Nature Protocols 2015).
Despite increasing understand of their function, there are many UNSOLVED QUESTIONS. What is their function in the normal liver besides the storage of retinoids? What benefits do HSC activation and fibrosis confer? We do not believe that HSC activation and fibrosis would have evolved without conferring benefits to the host, at last in the short term. Thus, a major goal of our lab is to understand both PROTECTIVE and DISEASE-PROMOTING roles of HSC in mice and men.
A major focus hereby is the understanding of hepatic stellate cell biology in NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) and NON-ALCOHOLIC STEATOHEPATITIS (NASH). With NAFLD affecting about 2 billion people world-wide and fibrosis representing the main determinant of outcomes in NAFLD, understanding HSC in NASH in essential. We propose that shifting the balance from HSC-mediated disease promotion to HSC-mediated protection can serve as therapy for NASH. Likewise, we also apply this concept to HEPATOCELLULAR CARCINOMA (HCC) and have demonstrated that shifting the balance between disease-promoting and protective functions of HSC can prevent the development of HCC (Filliol et al, Nature 2022).
Liver cancer is the third leading cause of cancer death world-wide - the majority of deaths (about 800,000/year) due to hepatocellular carcinoma (HCC). We have witnessed significant advances in the medical therapy of HCC, but nearly all medical therapies (checkpoint inhibitors; anti-angiogenic drugs; multi-kinase inhibitors) act largely or exclusively through the tumor microenvironment.
A recent goal of the Schwabe lab is to discover therapeutic vulnerabilities of HCC tumor cells - using above-described bioinformatic analyses from patients - and to combine this with genetic forward screens and mouse models to find drugs that directly target key pathway in HCC. The ultimate goal is to combine tumor cell-targeted therapies with the existing efficient TME-targeted therapies for highly efficient medical therapy of HCC (similar the amazing advances in the therapy of other solid tumors).
While the three above areas are our main focus, we have developed expertise in many additional areas in liver research - which is often needed to understand the interconnected and complex biology of liver disease. As such, we have strong expertise in liver regeneration, e.g. induced by partial hepatectomy; primary cell isolation and culture of nearly every liver cell type; genetic tagging and tracing of various liver cell types; induction of cholangiocarcinoma by hydrodynamic tail vein injection; induction of liver metastasis; the microbiome in liver fibrosis (Seki et al, Nat Med 2007) and HCC (Dapito et al, Cancer Cell 2012; Schwabe et al Nat Rev Cancer 2013).
Filliol et al, Nature. 2022 Oct;610(7931):356-365.
Here we demonstrated an overall tumor-promoting role of hepatic stellate cells (HSC) in the development of hepatocellular carcinoma (HCC), which resulted from a progressive imbalance between protective quiescent hepatic stellate cells (cyHSCs) and activated myofibroblastic HSCs (myHSCs). Importantly, myHSCs accumulated outside tumors/prior to tumor development and appeared to promote the development of tumors rather than the progression of already established larger tumors. Protection by cyHSC depended on hepatocyte growth factor (HGF) whereas tumor promotion by myHSC was largely mediated by type I collagen. In summary, our results suggest that restoring the dysbalance between protective cyHSC and tumor-promoting myHSC may reduce the risk for HCC development.
Affo et al, Cancer Cell. 2021 Jun 14;39(6):866-882
Here we showed a strong tumor-promoting role of cancer-associated fibroblasts (CAF). Genetic tracing and single cell RNA-seq analyses revealed hepatic stellate cells (HSC) as main source of CAF and hub of cell-cell communication in murine and human CCA. Depletion of CAF reduced tumor growth as did HSC-selective deletion of Hgf and Has2. Surprisingly, deletion of type I collagen did not affect the growth of this highly desmoplastic tumor. Our results suggest HSC-derived CAF as therapeutic target for this deadly tumor.
Bhattacharjee et al . J Clin Invest. 2021 Jun 1;131(11):e146987.
Here we investigated the role of cancer-associated fibroblasts (CAF) and type I collagen in desmoplastic colorectal and pancreatic liver metastasis. We demonstrated that - similar to cholangiocarcinoma - CAF were derived from hepatic stellate cells (HSC). ScRNA-seq demonstrated that HSC were a hub of cell-cell communication and intensely interacted with tumor cells. Depletion and HSC-selective knockout reveated that HSC promoted tumor growth and lethality, mediated by Hgf and Has2. However, CAF also restricted tumor growth through type I collagen. The tumor-restricting mechanical barrier provided by type I collagen overrides its tumor-promoting effects via induction of stiffness-induced mechanosignaling, e.g. YAP/TAZ.
Mederacke, Filliol, Affo et al, Sci Transl Med . 2022 Apr 6;14(639):eabe5795.
Hepatocyte death is closely associated with the development of liver fibrosis in patients and sufficient to trigger fibrosis in mice. Here, we hypothesized that damage-associated molecular patterns (DAMPs) may link epithelial cell death to fibrogenesis in the injured liver. We identified purinergic receptor P2Y14 among several candidates as highly enriched in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Conversely, P2Y14 ligands UDP-glucose and UDP-galactose were enriched in hepatocytes and were released upon different modes of cell death. Ligand-receptor interaction analysis, in vitro experiments with P2Y14 ligands and dead hepatocytes as well as in vivo studies in knockout mice demonstrated that P2Y14 ligands and their receptor constitute a profibrogenic DAMP pathway that directly links cell death to fibrogenesis in the liver.