We show here that the AAA +ATPase Reptin is a regulator of mTOR signalling in the liver and global glucido-lipidic homeostasis. Inhibition of hepatic Reptin expression or activity represents a new therapeutic perspective for metabolic syndrome.

The architecture of individual cells and cell collectives enables functional specification, a prominent example being the formation of epithelial tubes that transport fluid or gas in many organs. The intrahepatic bile ducts (IHBDs) form a tubular network within the liver parenchyma that transports bile to the intestine. Aberrant biliary 'neoductulogenesis' is also a feature of several liver pathologies including tumorigenesis. However, the mechanism of biliary tube morphogenesis in development or disease is not known. Elimination of the neurofibromatosis type 2 protein (NF2; also known as merlin or neurofibromin 2) causes hepatomegaly due to massive biliary neoductulogenesis in the mouse liver. We show that this phenotype reflects unlimited biliary morphogenesis rather than proliferative expansion. Our studies suggest that NF2 normally limits biliary morphogenesis by coordinating lumen expansion and cell architecture. This work provides fundamental insight into how biliary fate and tubulogenesis are coordinated during development and will guide analyses of disease-associated and experimentally induced biliary pathologies.

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Previous studies have shown that Reptin is overexpressed in hepatocellular carcinoma and that it is necessary for in vitro proliferation and cell survival. However, its pathophysiological role in vivo remains unknown. We aimed to study the role of Reptin in hepatocyte proliferation after regeneration using a liver Reptin knockout model (Reptin LKO ). Interestingly, hepatocyte proliferation is strongly impaired in

Introduction: The Antibody-Drug Conjugates (ADCs)-based therapy has revealed a field of perspectives by increasing the specificity and the efficacy of the anti-tumoral drug treatment. McSAF is a company focused in bio-organic and bioconjugates chemistry and has developed a new linker technology solution, allowing to improve ADCs homogeneity and stability resulting in a higher anti-tumoral effect on a HER2-positive breast tumor model (BT-474 cell line) and a CD30-positive non-Hodgkin's lymphoma model (Karpas-299 cell line). Methods: The anti-tumoral activity of McSAF-ADCs was tested both in vitro and in vivo. In both cell line models, an MTS-based cell viability assay has been performed in presence of the standard of care (SOC, Kadcyla® (T-DM1) = Trastuzumab emtansine, or Adcetris® = Brentuximab vedotin) or the equivalent McSAF-ADCs at different concentrations for 72 to 96 hours. In vivo studies were conducted with xenograft models of HER2-positive tumors in Balb-c nude mice and CD30-positive lymphoma in CB17 SCID mice. After tumor induction, animals bearing well-established tumors (≈100-200 mm3) were randomized and treated once or twice with vehicle, SOC or McSAF-ADCs at one or two doses. During the study course, the animals were monitored for several weeks for their behavior, body weight and tumor volume. Results: In the HER2-positive breast tumor model, in vitro experiments revealed a higher cytotoxicity of MF-TTZ-MMAE (IC50 = 1 nM) on BT-474 cell line compared to the SOC (IC50 ≈ 100 nM). In vivo, the treatment with MF-TTZ-MMAE was well tolerated at all tested doses (1 and 5 mg/kg). At 5 mg/kg, the MF-TTZ-MMAE compound induced a full regression of tumors after second treatment. At the end of the study, all animals treated with MF-TTZ-MMAE were still tumor free, seven weeks after end of treatment, which was not observed on animals treated with T-DM1 (only 25% tumor-free animals). In the CD30-positive non-Hodgkin's lymphoma model, the MTS assay revealed similar efficacy for brentuximab vedotin and MF-BTX-MMAE (IC50 ≈ 0.1 nM) on Karpas-299 cell line. In vivo, the treatment with MF-BTX-MMAE was well tolerated at all tested doses (0.5 and 1 mg/kg). The single treatment with MF-BTX-MMAE had a marked, dose dependent, anti-tumoral efficacy with 40% and 100% of animals showing complete regression at the end of the study (9 weeks after treatment) for doses of 0.5 mg/kg and 1 mg/kg respectively. And again, the treatment with MF-BTX-MMAE at 0.5 mg/kg resulted in a higher tumor growth inhibition and better survival than with the clinical equivalent ADC Adcetris® at the equivalent dose. Conclusion: Altogether, these promising results reveal that improvement of ADCs stability and homogeneity leads to a higher anti-tumoral activity as tested both in vitro and in vivo HER2-positive and CD30-positive tumor models. Citation Format: Jean-Francois Mirjolet, Audrey Bertaux, Samira Benhamouche-Trouillet, Pascal Grondin, Ambrine Sahal, Guillaume Serin, Ludovic Juen, Christine Baltus, Camille Gély, Ofelia Feuillâtre, Audrey Desgranges, Marie-Claude Viaud-Massuard, Camille Martin. ADCs optimization lead to a significant anti-tumoral activity in lymphoma and breast tumor xenograft mouse models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4115.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death and accounts for >80% of primary liver cancer worldwide. Early stage HCC can be treated by local ablation, surgical resection or liver transplantation. Systemic pharmacological options are limited and only a few available (kinase and immune-checkpoint inhibitors). Most cases of liver cancer occur in the setting of chronic liver diseases. Risk factors include chronic Hepatitis B and C, alcohol addiction and metabolic diseases. HCC is a multistep process comprising chronic liver injury, inflammation, fibrosis/cirrhosis and cancer formation. Therefore, providing palliative and curative options remains a high medical need. In order to better evaluate new preventive and curative treatments of liver cancers we developed complementary and integrated strategies to mimic the liver cancer initiation and progression steps in mouse models. These models involve chemotoxic agents, diet-induced disorders and implantation strategies. We first established an orthotopic syngeneic model using Hepa1.6 mouse liver hepatoma cells. Hepa1.6-derived tumor growth was characterized through liver index, alpha-fetoprotein measurement in serum and liver, and MRI. The response to chemotherapy (Sorafenib) and immunotherapy (anti PD-1) was also assessed. Moreover, a panel of Patient-Derived Xenograft models (PDXs) are available to assess new treatment options in human HCC with regards of the genetic mutations and the variety of etiologies seen in human. During the course of HCC formation, the liver undergoes cycles of inflammation, necrosis with regeneration, fibrosis, cell dysplasia and ultimately HCC. Thus, we developed two models of non- alcoholic steato-hepatitis (NASH); The first model involves chronic administration of hepatotoxic CCL4 associated with a high-fat and high-fructose diet. Mice develop steatohepatitis and fibrosis within 4 to 8 weeks as assessed with biochemistry parameters (AST, ALT…), gene expression levels of inflammatory and fibrotic genes as well as histological scores and MRI. The effect of obeticholic acid was successfully evaluated in this model. The second model is the STAM model induced by a low dose of Streptozotocin and high fat diet regimen. In this model, mice develop metabolic syndrome (increased body weight gain, hyperglycemia and hyperlipidemia), NASH (steatosis, inflammation, fibrosis) within 12 weeks and HCC within 16 weeks. The responses to standard of care and to immunotherapy together with the characterization of the immune cell populations are currently under investigation. Altogether, these results demonstrate the usefulness of this liver diseases development program to discover and identify new treatments that could circumvent the progression of liver cancer. Citation Format: Olivier Duchamp, Gael Krysa, Robin Artus, Hugo Quillery, Maxime Ramelet, Valerie Boullay, Laure Levenez, Adelaide Ferment, Jeremy Odillard, Anne-Benedict Boullay, Peggy Provent, Edwige Nicodeme, Samira Benhamouche-Trouillet, Anne Lazzari, Loic Morgand. Liver preclinical models - acute, chronic and cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5638.

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Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death and accounts for over 80% of primary liver cancer worldwide. Early stage HCC can be treated by local ablation, surgical resection or liver transplantation. Systemic pharmacological options are limited (kinase and immune-checkpoint inhibitors). Most cases of liver cancer occur in the setting of chronic liver diseases. Risk factors include chronic Hepatitis B and C, alcohol addiction and metabolic diseases. HCC is a multistep process comprising chronic liver injury, inflammation, fibrosis/cirrhosis and cancer formation. Therefore, providing palliative and curative options remains a high medical need. And with the recent success of immunotherapies in HCC, mouse models that better recapitulate the human disease and antitumor immune response are needed. In order to better evaluate new preventive and curative treatments of liver cancers we developed complementary and integrated strategies to mimic the liver cancer initiation and progression steps in mouse models. These models involve chemotoxic agents, diet-induced disorders and syngeneic or xenogeneic tumor implantation strategies. We established an orthotopic syngeneic model using Hepa1.6 mouse liver hepatoma cells, characterized through liver index, alpha-fetoprotein measurement in serum and liver, and MRI. The response to chemotherapy (sorafenib) and immunotherapy (anti PD-1, anti-TLR) was also assessed and show moderate to high efficiency. Moreover, a panel of xenograft models including Patient-Derived Xenograft models (PDXs) are available to assess new treatment options in human HCC with regards of the genetic mutations and the variety of etiologies seen in human. But as xenograft models are not completely mimicking the human situation of both immune and liver microenvironment, we have recently initiated the development of a double humanized (immune and liver) transgenic mouse as a better host for human tumor engraftment. During the course of HCC formation, the liver undergoes cycles of inflammation, necrosis with regeneration, fibrosis, cell dysplasia and ultimately HCC. Thus, we developed a model induced by a low dose of streptozotocin and high fat diet regimen. In this model, mice develop metabolic syndrome NASH and fibrosis within 12 weeks and HCC within 16 weeks. Of interest, 100% of male mice develop HCC within 16 weeks, in accordance with studies showing that men had a 2-to 7-fold higher risk of developing HCC in human. Treatment of mice with lenvatinib alone or in combination with anti-PD1 increases survival and reduces tumor burden as shown with reduced liver weight/body weight ratio at 16 weeks. Altogether, these results demonstrate the usefulness of this comprehensive platform of preclinical in vivo HCC models to discover and identify novel therapeutic strategies that could circumvent the progression of liver cancers. Citation Format: Olivier Duchamp, Gael Krysa, Loic Morgand, Hugo Quillery, Robin Artus, Maxime Ramelet, Jeremy Odillard, Peggy Provent, Sylvie Maubant, Caroline Mignard, Fabrice Viviani, Samira Benhamouche-Trouillet. Mouse models of hepatocellular carcinoma: A comprehensive and functional preclinical platform for immunotherapy research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1654.