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Decrypting the Mechanisms of Tumor Progression in Low Grade Human Hepatocellular Carcinomas. Décryptage des Mécanismes de Progression Tumorale dans les Carcinomes Hépatocellulaires de Bas Grade chez l’Homme
Résumé du sujet :Hepatocellular carcinoma (HCC) is the 3rd cause of cancer death worldwide and its heterogeneity challenges patient management. Prediction of early recurrence and of the potential for cancer aggressiveness are key factors governing patient eligibility for potentially curative therapies.1 Last year, after analysis of 1133 human HCCs, we reported a 2-dimensional distribution explaining HCC heterogeneity.2 We defined a 1st dimension across the proliferation/differentiation ratio, with progressive tumor dedifferentiation and development of tumor fibrosis and cancer stem cells, in accordance with our previous modeling.3-5 In the 2nd dimension, we showed that well-differentiated HCCs distribute across an HNF4α/β-catenin-driven metabolic, hepatocyte-specific axis. As a result, we identified four HCC subclasses: PERIPORTAL, PERIVENOUS, EXTRACELLULAR MATRIX and STEM CELL, that form a continuum of increasing malignancy. Our discovery was showcased in an editorial article in Hepatology and appeared on the November 2017 cover page;6 hence attesting to its novelty and significance. The salient finding of this work was the discovery of the least aggressive of all HCC subclasses (PERIPORTAL-TYPE HCCs). PERIPORTAL-TYPE HCCs represent 30% of all resected HCCs. They are defined by the high expression of eight liver-specific gene markers involved in periportal liver metabolic functions, such as gluconeogenesis and amino-acid catabolism (INSERM PATENT). Seventy percent of PERIPORTAL-TYPE HCCs and 60% of PERIVENOUS-TYPE HCCs did not recur two years after resection.2 This tumor behavior indicates low malignancy HCCs. However, 30% of PERIPORTAL-TYPE and 40% of PERIVENOUS-TYPE HCCs progress to high-grade cancers. Therefore, the Master Internship aims to be a step forward in a program investigating how low grade cancers acquire further malignancy and end up killing the patients. This project is being carried out by researchers in bio-statistics, anatomical pathologists, research engineers and molecular biologists, with both heuristics and translational purposes in cancer research.

References
1. Sapisochin G, Bruix J: Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches, Nat Rev Gastroenterol Hepatol 2017, 14:203-217
2. Desert R, Rohart F, Canal F, Sicard M, Desille M, Renaud S, Turlin B, Bellaud P, Perret C, Clement B, Le Cao KA, Musso O: Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection, Hepatology 2017, 66:1502-1518
3. Desert R, Mebarki S, Desille M, Sicard M, Lavergne E, Renaud S, Bergeat D, Sulpice L, Perret C, Turlin B, Clement B, Musso O: « Fibrous nests » in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome, Int J Biochem Cell Biol 2016,
4. Mebarki S, Desert R, Sulpice L, Sicard M, Desille M, Canal F, Dubois-Pot Schneider H, Bergeat D, Turlin B, Bellaud P, Lavergne E, Le Guevel R, Corlu A, Perret C, Coulouarn C, Clement B, Musso O: De novo HAPLN1 expression hallmarks Wnt-induced stem cell and fibrogenic networks leading to aggressive human hepatocellular carcinomas, Oncotarget 2016, 7:39026-39043
5. Dubois-Pot-Schneider H, Fekir K, Coulouarn C, Glaise D, Aninat C, Jarnouen K, Le Guevel R, Kubo T, Ishida S, Morel F, Corlu A: Inflammatory cytokines promote the retrodifferentiation of tumor-derived hepatocyte-like cells to progenitor cells, Hepatology 2014, 60:2077-2090
6. Ng CKY, Piscuoglio S, Terracciano LM: Molecular classification of hepatocellular carcinoma: The view from metabolic zonation, Hepatology 2017, 66:1377-1380

Laboratoire d’accueil Institut NuMeCan
Equipe d’accueil EXPRES
Responsable(s) scientifique(s) Orlando MUSSO
Contact(s) orlando.musso@univ-rennes1.fr
Proposé le 14-06-2018

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