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Summary TxNIP (Thioredoxin-interacting protein) is considered as a potential drug target for type 2 diabetes. Although TxNIP expression is correlated with hyperglycemia and glucotoxicity in pancreatic β cells, its regulation in liver cells has been less investigated. In the current study, we aim at providing a better understanding of Txnip regulation in hepatocytes in response to physiological stimuli and in the context of hyperglycemia in db/db mice. We focused on regulatory pathways governed by ChREBP (Carbohydrate Responsive Element Binding Protein) and FoxO1 (Forkhead box protein O1), transcription factors that play central roles in mediating the effects of glucose and fasting on gene expression, respectively. Studies using genetically modified mice reveal that hepatic TxNIP is up-regulated by both ChREBP and FoxO1 in liver cells and that its expression strongly correlates with fasting, suggesting a major role for this protein in the physiological adaptation to nutrient restriction., Graphical abstract, Highlights • TxNIP is considered as a potential candidate drug target for type 2 diabetes • We provide better understanding of Txnip regulation and function in liver • Hepatic Txnip is up-regulated by both ChREBP and FoxO1 transcription factors • We suggest a role for TxNIP in the physiological adaptation to nutrient restriction, Molecular Physiology ; Molecular Biology ; Endocrinology

Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis.Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model.Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model.Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials.Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.

DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) that occurs in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered.A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome sequencing. Western blots were performed to validate genomic discoveries. Results were validated using the TCGA database.Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors, which all had mutations or translocations inactivating BAP1, the gene encoding BRCA1-associated protein-1. Like FLC, BAP1-HCC were significantly enriched in females, patients with a lack of chronic liver disease, and fibrotic tumors compared to non-BAP1 HCC. However, patients were older and had a poorer prognosis than those with FLC. BAP1 tumors were immune hot, showed progenitor features and did not show DNAJB1-PRKACA fusion, while almost none of these tumors had mutations in CTNNB1, TP53 and TERT promoter. In contrast, 80% of the BAP1 tumors showed a chromosome gain of PRKACA at 19p13, combined with a loss of PRKAR2A (coding for the inhibitory regulatory subunit of PKA) at 3p21, leading to a high PRKACA/PRKAR2A ratio at the mRNA and protein levels.We have characterized a subgroup of BAP1-driven HCC with fibrolamellar-like features and a dysregulation of the PKA pathway, which could be at the root of the clinical and histological similarities between BAP1 tumors and DNAJB1-PRKACA FLCs.Herein, we have defined a homogeneous subgroup of hepatocellular carcinomas in which the BAP1 gene is inactivated. This leads to the development of cancers with features similar to those of fibrolamellar carcinoma. These tumors more frequently develop in females without chronic liver disease or cirrhosis. The presence of PKA activation and T cell infiltrates suggest that these tumors could be treated with PKA inhibitors or immunomodulators.

Relapsed and metastatic hepatoblastoma represents an unmet clinical need with limited chemotherapy treatment options. In a chemical screen, we identified volasertib as an agent with in vitro activity, inhibiting hepatoblastoma cell growth while sparing normal hepatocytes. Volasertib targets PLK1 and prevents the progression of mitosis, resulting in eventual cell death. PLK1 is overexpressed in hepatoblastoma biopsies relative to normal liver tissue. As a potential therapeutic strategy, we tested the combination of volasertib and the relapse-related hepatoblastoma chemotherapeutic irinotecan. We found both in vitro and in vivo efficacy of this combination, which may merit further preclinical investigation and exploration for a clinical trial concept.

Resume Le lait est un produit vivant, il subit donc des traitements, le plus souvent thermiques, qui permettent une meilleure conservation. Le lait est un aliment naturellement riche en proteines de haute valeur biologique, en calcium, en vitamines et oligo-elements. Sa place dans notre alimentation est donc justifiee, elle varie selon les âges de la vie. Le repere de consommation du Programme National Nutrition Sante (PNNS) est de trois produits laitiers par jour.

Tumour heterogeneity is probably the reason for different sensitivity to the same treatment in patients. Therefore, we urgently need to develop tools to help assign the right treatment to the right patient. This is particularly challenging for paediatric cancers. Hepatoblastoma (HB) is the most frequent malignant embryonal tumor of the liver in childhood. About 25% of HB patients will develop metastatic disease which is associated with a poor prognosis. Because of the small number of patients eligible for enrollment, clinical trials in most of cases could not provide clinicians with statistically significant results. In oncology, preclinical data are generally poorly predictive of treatment efficacy in patients, probably due to oversimplification of tumor biology and underrepresentation of the genetic tumor heterogeneity observed in patients. To face this issue, we have launched a program to generate patient-derived xenografts, the gold standard in preclinical oncology, from surgical tissue from HB patients after chemotherapy, at relapse and from local and distant metastases. Therefore, the models developed are representative of relapsing, metastatic HB. So far, a panel of 24 HB PDXs models has been established. From these models 10 cell lines could be established so far to be used for large-scale in vitro screening of anticancer compound libraries. The aim of this project is to combine in vitro and in vivo drug screening to provide strong preclinical rationale to the development of novel therapeutic options for children with HB, and to identify candidate biomarkers predictive of tumor response. In vitro screening of a HB PDX-derived cells with a library of 60 compounds corresponding to treatments already available in the clinic lead us to identify 4 compounds with very strong cytotoxic activity on HB cells. One of them, Volasertib, a PLK1 inhibitor, was selected to be tested in the HB PDX the cells were derived from. The in vivo study compared the effect of volasertib as single agent or in combination with irinotecan to irinotecan alone or in combination with temozolomide. The results showed that high dose volasertib induce tumor regression with efficacy comparable to irinotecan/temozolomide combination. Following these encouraging results, Volasertib was tested in the complete panel of HB PDX-derived cells, and the majority of them showed strong sensitivity to the drug. This sensitivity was associated with specific molecular alterations that might be used as biomarkers to predict tumor sensitivity. Overall, these results suggest that volasertib could be an effective second line treatment for children with recurrent HB, and that this platform could be a very important preclinical tool to foster translational research in HB. Citation Format: Stefano Cairo, Bénédicte Noblet, Samuel Rasmussen, Matthew N. Svalina, Katell Mevel, Enora Le Ven, Delphine Nicolle, Olivier Déas, Charlotte Mussini, Sophie Branchereau, Jean-Gabriel Judde, Charles Keller. Tailoring personalized strategies for children with treatment-refractory liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4628.