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The TGF-beta1 target WISP1 is highly expressed in liver cirrhosis and cirrhotic HCC microenvironment and involved in pro- and anti-tumorigenic effects.

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INTRODUCTION: WNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the … progression of chronic liver diseases (CLD) was investigated. METHODS: WISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells. RESULTS: In a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-beta1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells. CONCLUSIONS: WISP1 expression is induced by TGF-beta1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD.

Authors: A. Dropmann, S. Alex, K. Schorn, C. Tong, T. Caccamo, P. Godoy, I. Ilkavets, R. Liebe, D. Gonzalez, J. G. Hengstler, A. Piiper, L. Quagliata, M. S. Matter, O. Waidmann, F. Finkelmeier, T. Feng, T. S. Weiss, N. Rahbari, E. Birgin, E. Rasbach, S. Roessler, K. Breuhahn, M. Toth, M. P. Ebert, S. Dooley, S. Hammad, N. M. Meindl-Beinker

Date Published: 5th Nov 2024

Publication Type: Journal

Hepatocellular Cancer Surveillance in Patients with Advanced Chronic Liver Disease.

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BACKGROUND: Patients with advanced chronic liver disease (ACLD) are at high risk of developing hepatocellular carcinoma (HCC). Therefore, biannual surveillance is recommended. This large-scale multicenter … study aimed to stratify the risk of HCC development in ACLD. METHODS: From 3016 patients with ACLD screened in 17 European and Chinese centers, 2340 patients with liver stiffness measurement (LSM) determined using different techniques (two-dimensional shear-wave elastography [2D-SWE], transient elastography, and point shear-wave elastography) and with different disease severities were included. Cox regression was used to explore risk factors for HCC. We used these data to create an algorithm, named PLEASE, but referred to in this manuscript as "the algorithm"; the algorithm was validated in internal and two external cohorts across elastography techniques. RESULTS: HCC developed in 127 (5.4%) patients during follow-up. LSM by 2D-SWE (hazard ratio: 2.28) was found to be associated with developing HCC, alongside age, sex, etiology, and platelet count (C-index: 0.8428). We thus established the algorithm with applicable cutoffs, assigning a maximum of six points: platelet count less than 150x10(9)/l, LSM greater than or equal to 15 kPa, age greater than or equal to 50 years, male sex, controlled/uncontrolled viral hepatitis, or presence of steatotic liver diseases. Within 2 years, with a median follow-up of 13.7 months, patients in the high-risk group (>/=4 points) had an HCC incidence of 15.6% (95% confidence interval [CI], 12.1% to 18.7%) compared with the low-risk group, at 1.7% (95% CI, 0.9% to 2.5%). CONCLUSIONS: Our algorithm stratified patients into two groups: those at higher risk of developing HCC and those at lower risk. Our data provide equipoise to test the prospective utility of the algorithm with respect to clinical decisions about screening patients with ACLD for incident HCC. (Funded by the German Research Foundation and others; ClinicalTrials.gov number, NCT03389152.).

Authors: W. Gu, V. de Ledinghen, C. Aube, A. Krag, C. Strassburg, L. Castera, J. Dumortier, M. Friedrich-Rust, S. Pol, I. Grgurevic, Y. Zeleke, M. Praktiknjo, R. Schierwagen, S. Klein, S. Francque, H. Gottfriedova, I. Sporea, P. Schindler, F. Rennebaum, M. J. Brol, M. Schulz, F. E. Uschner, J. Fischer, C. Margini, W. Wang, A. Delamarre, J. Best, A. Canbay, D. J. M. Bauer, B. Simbrunner, G. Semmler, T. Reiberger, J. Boursier, D. N. Rasmussen, V. Vilgrain, A. Guibal, S. Zeuzem, C. Vassord, L. Vonghia, R. Senkerikova, A. Popescu, A. Berzigotti, W. Laleman, M. Thiele, C. Jansen, J. Trebicka

Date Published: 22nd Oct 2024

Publication Type: Journal

Direct Ingestion of Oxidized Red Blood Cells (Efferocytosis) by Hepatocytes.

Abstract (Expand)

PURPOSE: Both hepatic iron accumulation and hemolysis have been identified as independent prognostic factor in alcohol-related liver disease (ALD); however, the mechanisms still remain poorly understood. … We here demonstrate that hepatocytes are able to directly ingest aged and ethanol-primed red blood cells (RBCs), a process termed efferocytosis. METHODS: Efferocytosis of RBCs was directly studied in vitro and observed by live microscopy for real-time visualization. RBCs pretreated with either CuSO(4) or ethanol following co-incubation with Huh7 cells and murine primary hepatocytes. Heme oxygenase-1 (HO-1) and other targets were measured by q-PCR. RESULTS: As shown by live microscopy, oxidized RBCs, but not intact RBCs, are rapidly ingested by both Huh7 cells and murine primary hepatocytes within 10 minutes. In some cases, more than 10 RBCs were seen within hepatocytes, surrounding the nucleus. RBC efferocytosis also rapidly induces HO1, its upstream regulator Nuclear factor erythroid 2-related factor 2 (Nrf2) and ferritin, indicating efficient heme degradation. Preliminary data further suggest that hepatocyte efferocytosis of oxidized RBCs is, at least in part, mediated by scavenging receptors such as ASGPR1. Of note, pretreatment of RBCs with ethanol but also heme and bilirubin also initiated efferocytosis. In a cohort of heavy human drinkers, a significant correlation of hepatic ASGPR1 with the heme degradation pathway was observed. CONCLUSION: We here demonstrate that hepatocytes can directly ingest and degrade oxidized RBCs through efferocytosis, a process that can be also triggered by ethanol, heme and bilirubin. Our findings are highly suggestive for a novel mechanism of hepatic iron overload in ALD patients.

Authors: C. Zheng, S. Li, H. Lyu, C. Chen, J. Mueller, A. Dropmann, S. Hammad, S. Dooley, S. He, S. Mueller

Date Published: 9th Sep 2024

Publication Type: Journal

Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure.

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BACKGROUND: When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The … underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF. METHODS: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF. RESULTS: Under ALF conditions, activated HSCs secreted RA, inducing RARalpha nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-beta-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARalpha nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARalpha nuclear translocation in the LPCs had significantly better MELD scores than those without. CONCLUSIONS: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.

Authors: S. Wang, F. Link, S. Munker, W. Wang, R. Feng, R. Liebe, Y. Li, Y. Yao, H. Liu, C. Shao, M. P. A. Ebert, H. Ding, S. Dooley, H. L. Weng, S. S. Wang

Date Published: 1st Aug 2024

Publication Type: Journal

Tumour-specific activation of a tumour-blood transport improves the diagnostic accuracy of blood tumour markers in mice.

Abstract (Expand)

BACKGROUND: The accuracy of blood-based early tumour recognition is compromised by signal production at non-tumoral sites, low amount of signal produced by small tumours, and variable tumour production. … Here we examined whether tumour-specific enhancement of vascular permeability by the particular tumour homing peptide, iRGD, which carries dual function of binding to integrin receptors overexpressed in the tumour vasculature and is known to promote extravasation via neuropilin-1 receptor upon site-specific cleavage, might be useful to improve blood-based tumour detection by inducing a yet unrecognised vice versa tumour-to-blood transport. METHODS: To detect an iRGD-induced tumour-to-blood transport, we examined the effect of intravenously injected iRGD on blood levels of alpha-fetoprotein (AFP) and autotaxin in several mouse models of hepatocellular carcinoma (HCC) or in mice with chronic liver injury without HCC, and on prostate-specific antigen (PSA) levels in mice with prostate cancer. FINDINGS: Intravenously injected iRGD rapidly and robustly elevated the blood levels of AFP in several mouse models of HCC, but not in mice with chronic liver injury. The effect was primarily seen in mice with small tumours and normal basal blood AFP levels, was attenuated by an anti-neuropilin-1 antibody, and depended on the concentration gradient between tumour and blood. iRGD treatment was also able to increase blood levels of autotaxin in HCC mice, and of PSA in mice with prostate cancer. INTERPRETATION: We conclude that iRGD induces a tumour-to-blood transport in a tumour-specific fashion that has potential of improving diagnosis of early stage cancer. FUNDING: Deutsche Krebshilfe, DKTK, LOEWE-Frankfurt Cancer Institute.

Authors: C. Schmithals, B. Kakoschky, D. Denk, M. von Harten, J. H. Klug, E. Hintermann, A. Dropmann, E. Hamza, A. C. Jacomin, J. U. Marquardt, S. Zeuzem, P. Schirmacher, E. Herrmann, U. Christen, T. J. Vogl, O. Waidmann, S. Dooley, F. Finkelmeier, A. Piiper

Date Published: 13th Jul 2024

Publication Type: Journal

Comprehensive evaluation of phosphoproteomic-based kinase activity inference (preprint)

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Kinases play a central role in regulating cellular processes, making their study essential for understanding cellular function and disease mechanisms. To investigate the regulatory state of a kinase, … numerous methods have been, and continue to be, developed to infer kinase activities from phosphoproteomics data. These methods usually rely on a set of kinase targets collected from various kinase-substrate libraries. However, only a small percentage of measured phosphorylation sites can usually be attributed to an upstream kinase in these libraries, limiting the scope of kinase activity inference. In addition, the inferred activities from different methods can vary making it crucial to evaluate them for accurate interpretation. Here, we present a comprehensive evaluation of kinase activity inference methods using multiple kinase-substrate libraries combined with different inference algorithms. Additionally, we try to overcome the coverage limitations for measured targets in kinase substrate libraries by adding predicted kinase-substrate interactions for activity inference. For the evaluation, in addition to classical cell-based perturbation experiments, we introduce a tumor-based benchmarking approach that utilizes multi-omics data to identify highly active or inactive kinases per tumor type. We show that while most computational algorithms perform comparably regardless of their complexity, the choice of kinase-substrate library can highly impact the inferred kinase activities. Hereby, manually curated libraries, particularly PhosphoSitePlus, demonstrate superior performance in recapitulating kinase activities from phosphoproteomics data. Additionally, in the tumor-based evaluation, adding predicted targets from NetworKIN further boosts the performance, while normalizing sites to host protein levels reduces kinase activity inference performance. We then showcase how kinase activity inference can help in characterizing the response to kinase inhibitors in different cell lines. Overall, the selection of reliable kinase activity inference methods is important in identifying deregulated kinases and novel drug targets. Finally, to facilitate the evaluation of novel methods in the future, we provide both benchmarking approaches in the R package benchmarKIN.

Authors: Sophia Müller-Dott, Eric J. Jaehnig, Khoi Pham Munchic, Wen Jiang, Tomer M. Yaron-Barir, Sara R. Savage, Martin Garrido-Rodriguez, Jared L. Johnson, Alessandro Lussana, Evangelia Petsalaki, Jonathan T. Lei, Aurélien Dugourd, Karsten Krug, Lewis C. Cantley, D. R. Mani, Bing Zhang, Julio Saez-Rodriguez

Date Published: 2nd Jul 2024

Publication Type: Journal

Thy‐1 restricts steatosis and liver fibrosis in steatotic liver disease

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Abstract Background and Aims Steatotic liver disease (SLD) is generally considered to represent a hepatic manifestation of metabolic syndrome and includes a disease spectrum comprising isolated steatosis, …ludes a disease spectrum comprising isolated steatosis, metabolic dysfunction‐associated steatohepatitis, liver fibrosis and ultimately cirrhosis. A better understanding of the detailed underlying pathogenic mechanisms of this transition is crucial for the design of new and efficient therapeutic interventions. Thymocyte differentiation antigen (Thy‐1, also known as CD90) expression on fibroblasts controls central functions relevant to fibrogenesis, including proliferation, apoptosis, cytokine responsiveness, and myofibroblast differentiation. Methods The impact of Thy‐1 on the development of SLD and progression to fibrosis was investigated in high‐fat diet (HFD)‐induced SLD wild‐type and Thy‐1‐deficient mice. In addition, the serum soluble Thy‐1 (sThy‐1) concentration was analysed in patients with metabolic dysfunction‐associated SLD stratified according to steatosis, inflammation, or liver fibrosis using noninvasive markers. Results We demonstrated that Thy‐1 attenuates the development of fatty liver and the expression of profibrogenic genes in the livers of HFD‐induced SLD mice. Mechanistically, Thy‐1 directly inhibits the profibrotic activation of nonparenchymal liver cells. In addition, Thy‐1 prevents palmitic acid‐mediated amplification of the inflammatory response of myeloid cells, which might indirectly contribute to the pronounced development of liver fibrosis in Thy‐1‐deficient mice. Serum analysis of patients with metabolically associated steatotic liver disease syndrome revealed that sThy‐1 expression is correlated with liver fibrosis status, as assessed by liver stiffness, the Fib4 score, and the NAFLD fibrosis score. Conclusion Our data strongly suggest that Thy‐1 may function as a fibrosis‐protective factor in mouse and human SLD.

Authors: Valentin Blank, Thomas Karlas, Ulf Anderegg, Johannes Wiegand, Josi Arnold, Linnaeus Bundalian, Gabriela‐Diana Le Duc, Christiane Körner, Thomas Ebert, Anja Saalbach

Date Published: 4th May 2024

Publication Type: Journal

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress

Abstract

Not specified

Authors: Yoon Seok Jung, Kamalakannan Radhakrishnan, Seddik Hammad, Sebastian Müller, Johannes Müller, Jung-Ran Noh, Jina kim, In-Kyu Lee, Sung Jin Cho, Don-Kyu Kim, Yong-Hoon Kim, Chul-Ho Lee, Steven Dooley, Hueng-Sik Choi

Date Published: 1st Mar 2024

Publication Type: Journal

Lysis buffer selection guidance for mass spectrometry-based global proteomics including studies on the intersection of signal transduction and metabolism (preprint)

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Prerequisite for a successful proteomics experiment is a high-quality lysis of the sample of interest, resulting in a large number of identified proteins as well as a high coverage of protein sequences. … Therefore, the choice of suitable lysis conditions is crucial. Many buffers were previously employed in proteomics studies, yet a comprehensive comparison of lysate preparation conditions was so far missing. In this study, we compared the efficiency of four commonly used lysis buffers, containing the agents NP40, SDS, urea or GdnHCl, in four different types of biological samples (suspension and adherent cell lines, primary mouse cells and mouse liver tissue). After liquid chromatography-mass spectrometry (LC-MS) measurement and MaxQuant analysis, we compared chromatograms, intensities, number of identified proteins and the localization of the identified proteins. Overall, SDS emerged as the most reliable reagent, ensuring stable performance and reproducibility across diverse samples. Furthermore, our data advocated for a dual-sample lysis approach, including that the resulting pellet is lysed again after the initial lysis with a urea lysis buffer and subsequently both lysates are combined for a single LC-MS run to maximize the proteome coverage. However, none of the investigated lysis buffers proved to be superior in every category, indicating that the lysis buffer of choice depends on the proteins of interest and on the biological question. Further, we demonstrated with our systematic studies the establishment of conditions that allows to perform global proteomics and affinity purification-based interactome characterization from the same lysate. In sum our results provide guidance for the best-suited lysis buffer for mass spectrometry-based proteomics depending on the question of interest.

Authors: Barbara Helm, Pauline Hansen, Li Lai, Luisa Schwarzmüller, Simone M. Clas, Annika Richter, Max Ruwolt, Fan Liu, Dario Frey, Lorenza A. D’Alessandro, Wolf-Dieter Lehmann, Marcel Schilling, Dominic Helm, Dorothea Fiedler, Ursula Klingmüller

Date Published: 21st Feb 2024

Publication Type: Journal

EGF/STAT1 signals to maintain ECM1 expression in hepatic homeostasis are disrupted by IFNγ/NRF2 in chronic liver disease

Abstract (Expand)

Objective In healthy livers, latent transforming growth factor-β (LTGF-β) is stored in the extracellular matrix and kept quiescent by extracellular matrix protein 1 (ECM1). Upon damage, ECM1 is …age, ECM1 is downregulated in hepatocytes, facilitating LTGF-β activation and hepatic fibrosis. This study investigates the underlying molecular mechanisms by which ECM1 expression in the liver is controlled under patho-physiological conditions. Design In silico promoter analysis was used to predict pathways that regulate Ecm1 transcription. Functional assays were performed in AML12 cells, mouse and human primary hepatocytes (MPHs, HPHs), and in liver tissue of mice and patients. Results In healthy liver, EGF/Egfr signaling maintains Ecm1 expression through phosphorylation of Stat1 at S727, which promotes its binding to the Ecm1 gene promoter to enhance gene transcription. During liver inflammation, accumulated IFNγ interferes with EGF signaling by downregulating Egfr expression and by disrupting EGF/Egfr/Stat1-mediated Ecm1 promoter binding. Mechanistically, IFNγ induces Stat1 phosphorylation at position Y701, which is competing with the ability of p-Stat1 S727 to bind to the Ecm1 gene promoter. Additionally, IFNγ induces Nrf2 nuclear translocation and repressive binding to the Ecm1 gene promoter, thus further reducing Ecm1 expression. Importantly, patients suffering from liver cirrhosis who lack nuclear NRF2 expression consistently maintain higher levels of ECM1, inferring a better prognosis. Conclusion ECM1 expression in healthy livers is controlled by EGF/EGFR/STAT1 signaling. Upon liver injury, ECM1 expression is repressed by accumulating IFNγ/NRF2, leading to increased LTGF-β activation and the onset of hepatic fibrosis.

Authors: Yujia Li, Frederik Link, Weiguo Fan, Zeribe C. Nwosu, Weronika Pioronska, Kerry Gould, Christoph Meyer, Ye Yao, Seddik Hammad, Rilu Feng, Hui Liu, Chen Shao, Bing Sun, Huiguo Ding, Roman Liebe, Matthias P. A. Ebert, Hong-Lei Weng, Peter ten Dijke, Steven Dooley, Sai Wang

Date Published: 19th Feb 2024

Publication Type: Journal

A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage.

Abstract (Expand)

This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative … hypotheses about the interplay of different cell types on regeneration was simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types. We use deviations of observed trajectories from the simulated system to identify branching points, at which the systems behavior cannot be explained by the underlying set of hypotheses anymore. Our procedure reflects a successful strategy for generating a fully digital liver twin that, among others, permits to test perturbations from the molecular up to the tissue scale. The model simulations are complementing current knowledge on liver regeneration by identifying gaps in mechanistic relationships and guiding the system toward the most informative (lacking) parameters that can be experimentally addressed.

Authors: J. Zhao, A. Ghallab, R. Hassan, S. Dooley, J. G. Hengstler, D. Drasdo

Date Published: 16th Feb 2024

Publication Type: Journal

TGFβR1 inhibition drives hepatocellular carcinoma proliferation through induction of toll‐like‐receptor signalling

Abstract (Expand)

Abstract Transforming growth factor (TGF)‐β and toll‐like receptors (TLRs) have been shown to independently modulate the proliferation of hepatocellular carcinoma (HCC). Since a direct cross‐talk between … (HCC). Since a direct cross‐talk between these two signalling pathways in HCC has not been clearly described before, we aimed here to explore the possibility of such interaction. A human HCC tissue array ( n  = 20 vs. four control samples), human HCC samples ( n  = 10) and steatohepatitis‐driven murine HCC samples (control, NASH and HCC; n  = 6/group) were immunostained for TGFβR1, pSMAD2, TRAF6, IRAK1 and PCNA. The results were confirmed by immunoblotting. Effects of constant activation of the SMAD pathway by constitutive expression of ALK5 or knockdown of mediators of TLR signalling, IRAK1 and MyD88, on HCC proliferation, were investigated in the HCC cell line (HUH‐7) after treatment with TGFβ1 cytokine or TGFβR1 kinase inhibitor (LY2157299) using PCNA and MTS assay. TGFβR1 expression is decreased in human and murine HCC and associated with downregulated pSMAD2, but increased IRAK1, TRAF6 and PCNA staining. TGFβR1 kinase inhibition abolished the cytostatic effects of TGFβ1 and led to the induction of IRAK1, pIRAK1 and elevated mRNA levels of TLR‐9. Overexpression of ALK5 and knockdown of MyD88 or IRAK1 augmented the cytostatic effects of TGFβ1 on HUH‐7. In another epithelial HCC cell line, that is, HepG2, TGFβR1 kinase inhibitor similarly elevated cellular proliferation. There is a balance between the canonical SMAD‐driven tumour‐suppressing arm and the non‐canonical tumour‐promoting arm of TGFβ signalling. Disruption of this balance, by inhibition of the canonical pathway, induces HCC proliferation through TLR signalling.

Authors: Fatma El Zahraa Ammar Mohamed, Bedair Dewidar, Tao Lin, Matthias P. Ebert, Steven Dooley, Nadja M. Meindl‐Beinker, Seddik Hammad

Date Published: 8th Feb 2024

Publication Type: Journal

Impact of Viscosity on Human Hepatoma Spheroids in Soft Core–Shell Microcapsules

Abstract (Expand)

Abstract The extracellular environment regulates the structures and functions of cells, from the molecular to the tissue level. However, the underlying mechanisms influencing the organization and …ncing the organization and adaptation of cancer in three‐dimensional (3D) environments are not yet fully understood. In this study, the influence of the viscosity of the environment is investigated on the mechanical adaptability of human hepatoma cell (HepG2) spheroids in vitro, using 3D microcapsule reactors formed with droplet‐based microfluidics. To mimic the environment with different mechanical properties, HepG2 cells are encapsulated in alginate core–shell reservoirs (i.e., microcapsules) with different core viscosities tuned by incorporating carboxymethylcellulose. The significant changes in cell and spheroid distribution, proliferation, and cytoskeleton are observed and quantified. Importantly, changes in the expression and distribution of F‐actin and keratin 8 indicate the relation between spheroid stiffness and viscosity of the surrounding medium. The increase of F‐actin levels in the viscous medium can indicate an enhanced ability of tumor cells to traverse dense tissue. These results demonstrate the ability of cancer cells to dynamically adapt to the changes in extracellular viscosity, which is an important physical cue regulating tumor development, and thus of relevance in cancer biology.

Authors: Xuan Peng, Željko Janićijević, Sandy Lemm, Sandra Hauser, Michael Knobel, Jens Pietzsch, Michael Bachmann, Larysa Baraban

Date Published: 25th Jan 2024

Publication Type: Journal

Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease

Abstract (Expand)

Abstract Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) …otic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

Authors: Sebastian Burbano De Lara, Svenja Kemmer, Ina Biermayer, Svenja Feiler, Artyom Vlasov, Lorenza A D’Alessandro, Barbara Helm, Christina Mölders, Yannik Dieter, Ahmed Ghallab, Jan G Hengstler, Christiane Körner, Madlen Matz-Soja, Christina Götz, Georg Damm, Katrin Hoffmann, Daniel Seehofer, Thomas Berg, Marcel Schilling, Jens Timmer, Ursula Klingmüller

Date Published: 12th Jan 2024

Publication Type: Journal

ECM1-Mediated Inhibition of Protease-Induced LTGF-β1 Activation in Chronic Liver Disease: Implications for Therapeutic Strategies

Abstract

Not specified

Authors: Frederik Link, Yujia Li, Jieling Zhao, Stefan Munker, Weiguo Fan, Zeribe Nwosu, Ye Yao, Seddik Hammad, Roman Liebe, Peter ten Dijke, Honglei Weng, Matthias Ebert, Drik Drasdo, Steven Dooley, Sai Wang

Date Published: 2024

Publication Type: Journal

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