KRAS-mutated iCCA display distinct molecular alterations and a preferential sensitivity towards PARP-1 inhibition

Application of patient derived liver cancer cell lines for phenotypic characterization and therapeutic target identification

Murine liver organoids as a genetically flexible system to study liver cancer in vivo and in vitro.

The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5-year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)-lox system, RNA interference, …

Genetically flexible murine organoids for mechanistic and functional modeling of cholangiocarcinoma

Ginkgo biloba induces different gene expression signatures and oncogenic pathways in malignant and non-malignant cells of the liver

Ginkgo biloba (EGb761) is a widely used botanical drug. Several reports indicate that EGb761 confers preventive as well as anti-tumorigenic properties in a variety of tumors, including hepatocellular carcinoma (HCC). We here evaluate functional effects and molecular alterations induced by EGb761 in hepatoma cells and non-malignant hepatocytes. Hepatoma cell lines, primary human HCC cells and immortalized human hepatocytes (IH) were exposed to various concentrations (0-1000 μg/ml) of EGb761. Apoptosis and proliferation were evaluated after 72h of EGb761 exposure. Response to oxidative stress, tumorigenic properties and molecular changes were further investigated. While anti-oxidant effects w…

Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer

Background & Aims Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. Methods We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan–Meier curves. We analyze…

949 IDENTIFICATION OF TWO CLINICALLY DISTINCT SUBTYPES IN AUTOIMMUNE HEPATITIS BY COMPARATIVE FUNCTIONAL GENOMICS

Conclusion: Incidence of autoimmune hepatitis is increasing, as other autoimmune diseases in developed countries. The main recognised hypothesis is the ‘hygienist theory’ (improvement of hygien leading to a decrease in infections) with few putative non exclusive mechanisms involving antigenic competition, extension of immune regulation induced by exogenous bacterial antigen or Toll Like Receptors.

Abstract 1902: Enrichment of putative cancer stem cells during anti-angiogenic therapies promotes relapse formation in hepatocellular carcinoma

Abstract Background and Aims: Activation of neo-angiogenic processes in hepatocellular carcinoma (HCC) during disease progression is frequently associated with poor clinical outcome. Consequently, inhibition of neo-angiogenesis is an effective treatment strategy for advanced HCC. However, development of chemoresistance is observed in the majority of patients. Compelling evidence suggest that cancer stem cells (CSCs) may contribute to the acquisition of resistant properties in many solid tumors, but their exact role in this process for HCC remains to be defined. Here, we evaluate the importance of CSCs in the development of resistance and relapse formation after exposure to different anti-an…

Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML

Abstract Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death. Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort. Results: This study shows that relative BAX localization determine…

Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis

Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, and early (n = 5) and progressed (n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further em…

Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin.

Merlin is a versatile tumor suppressor protein encoded by the NF2 gene. Several lines of evidence suggest that Merlin exerts its tumor suppressor activity, at least in part, by forming an inhibitory complex with cluster of differentiation 44 (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to perturb the interaction of Merlin with CD44. We hypothesized that disruption of the Merlin-CD44 complex through loss of Merlin, unleashes putative tumor- or metastasis-promoting functions of CD44. To evaluate the relevance of the Merlin-CD44 interaction in vivo, we compared tumor growth and progression in Cd44-positive and Cd44-negative Nf2-mutant mice. Heterozygous Nf2-mut…

Activation of tumor initiating cells during anti-angiogenic therapies promotes tumor progression and relapse formation in hepatocellular carcinoma

Deletion of organic cation transporter Oct3 promotes hepatic fibrosis via upregulation of TGFβ

Organic cation transporters (OCT) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. OCTs are downregulated in cholestasis, fibrosis, and hepatocellular carcinoma, but the underlying molecular mechanisms and downstream effects of OCT deletion are unknown. Oct3-knockout ( Oct3−/−; FVB.Slc22a3tm10pb) and wild-type (WT; FVB) mice were subject to escalating doses of carbon tetrachloride (CCl4) or thioacetamide (TAA) for 6 wk to induce advanced parenchymal liver fibrosis. Secondary biliary fibrosis was generated by bile duct ligation. Liver fibrosis was assessed by hydroxyproline determination, quantitative Sirius red morp…

Application of Patient-Derived Liver Cancer Cells in Personalized Treatment Approach: Phenotypic Characterization and Therapeutic Target Identification

Integrative genomic analyses identified 14-3-3 zeta as a potential molecular driver of sorafenib resistance in HCC patients

The Co‐mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion‐Driven Cholangiocarcinoma

Background and aims Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and a highly lethal malignancy. Chemotherapeutic options are limited, but a considerable subset of patients harbors genetic lesions for which targeted agents exist. Fibroblast growth factor receptor 2 (FGFR2) fusions belong to the most frequent and therapeutically relevant alterations in ICC, and the first FGFR inhibitor was recently approved for the treatment of patients with progressed, fusion-positive ICC. Response rates of up to 35% indicate that FGFR-targeted therapies are beneficial in many but not all patients. Thus far, no established biomarkers exist that predict resistance or r…

Targeting tumor-initiating cells and compensatory YAP pathway to overcome sorafenib resistance in hepatocellular carcinoma

Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification.

Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long-term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were…