Recent publications, congrats Everyone!!!!!

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This rapidly evolving area has become a main focus of the Schwabe lab. We are using single cell and single nucleus RNA-seq and spatial transcriptomics 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 METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD - formerly NAFLD or "fatty liver"). With MASLD affecting about 2 billion people world-wide and fibrosis representing the main determinant of outcomes in MASLD, understanding metabolic HSC functions is essential. We propose that shifting  the balance from HSC-mediated disease promotion to HSC-mediated protection can serve as therapy for NASH (please see Sugmito, Saito et al Nature 2025; Schwabe and Brenner, Nat Rev Gastro Hepatol 2025 in press). 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).

Even the best current therapies extend median survival by only 1-2 months and the great majority of patients with cholangiocarcinoma die within the first 2 years.

The Schwabe lab seeks to develop novel combination therapies that prolong survival significantly longer than current therapies. With a combination of newly developed CRISPRi tools/screens and high throughput drug screening, we have uncovered therapies that can lead to a 5-fold increase in media survival in preclinical mouse models of cholangiocarcinoma. Further studies seek to combine these therapies with existing therapies and to characterize therapy-resistant persister cells.

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).