Chromatin organization is essential for appropriate interpretation of the genetic information. Here, we demonstrated that the chromatin associated proteins HP1 are dispensable for hepatocytes survival but are essential within hepatocytes to prevent liver tumor development in mice with HP1β being pivotal in these functions. Yet, we found that the loss of HP1 per se is not sufficient to induce cell transformation but renders cells more resistant to specific stress such as the expression of oncogenes and thus in fine, more prone to cell transformation. Molecular characterization of HP1-Triple KO pre-malignant livers and BMEL cells revealed that HP1 are essential for the maintenance of heterochromatin organization and for the regulation of specific genes with most of them having well characterized functions in liver functions and homeostasis. We further showed that some specific retrotransposons get reactivated upon loss of HP1, correlating with over-expression of genes in their neighborhood. Interestingly, we found that, although HP1-dependent genes are characterized by enrichment H3K9me3, this mark does not require HP1 for its maintenance and is not sufficient to maintain gene repression in absence of HP1. Finally, we demonstrated that the loss of TRIM28 association with HP1 recapitulated several phenotypes induced by the loss of HP1 including the reactivation of some retrotransposons and the increased incidence of liver cancer development. Altogether, our findings indicate that HP1 proteins act as guardians of liver homeostasis to prevent tumor development by modulating multiple chromatin-associated events within both the heterochromatic and euchromatic compartments, partly through regulation of the corepressor TRIM28 activity.

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KEYWORDSHemangioma; Mesenteric tumours; Magnetic resonance imaging; Pathology Case studyA 50-year old female with no remarkable medical history consulted her doctor because of persistent epigastric pain. The clinical examination was unremarkable and laboratory tests were normal.Ultrasonography revealed a subumbilical, homogeneous, echogenic mass with an axial diameter of 5 cm. The mass had regular margins, posterior acoustic enhancement, and no visible vascularisation on colour Doppler imaging.Computed tomography (CT) of the abdomen and pelvis before and after administration of iodinated contrast material showed a tissue mass located in the mesentery with regular margins, no calcification, no communication with the bowel loops, and attenuation values of 70 HU before injection. After intravenous administration of iodinated contrast material, CT demonstrated discontinuous, peripheral nodes that enhanced centripetally, with a dynamic pattern of enhancement identical to that of the aorta and which persisted during the delayed phase. Multiple vessels were visible within the mass including a branch of the superior mesenteric artery, but there was no thrombosis or obstruction (Fig. 1). No enlarged lymph node was visible.

Introduction: Pseudomyxoma peritonei (PMP) is a rare disease characterized by the progressive accumulation of mucinous ascites and peritoneal implants. The optimal treatment for PMP includes the association of complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). For patients with a large burdensome disease, the completeness of cytoreduction sometimes requires maximal effort surgery. The aim of this article is to provide proof of concept for two stage cytoreductive surgery (CRS) in this category of patients. Methods and materials: A two stage CRS and HIPEC with oxaliplatin was proposed for patients with bulky PMP including important involvement of the serosal surfaces of the bowel or colon who had an impaired nutritional status. The residual disease at the end of the first stage was less than 5 mm of thickness on several implants. Clinical, surgical and histopathological variables were analyzed. Results: All eight patients completed the two-stage strategy. Mortality was nil. One Clavien Dindo grade 3 event occurred in each stage. After a median follow up of 29.5 months, all patients were alive and free of recurrence. All of the patients had histopathological complete response on the specimens obtained from the residual sites during the second stage surgery. Conclusions: Two-stage surgical strategy is feasible for bulky PMP patients and it is associated with little high-grade morbidity and enhanced visceral sparing.

Chemoresistance, particularly to gemcitabine, is a major challenge in pancreatic cancer. The epidermal growth factor receptor (EGFR) and human epidermal growth factor receptors 2 and 3 (HER2, HER3) are expressed in many tumors, and they are relevant therapeutic targets due to their synergistic interaction to promote tumor aggressiveness and therapeutic resistance. Cocktails of antibodies directed against different targets are a promising strategy to overcome these processes. Here, we found by immunohistochemistry that these three receptors were co-expressed in 11% of patients with pancreatic adenocarcinoma. We then developed gemcitabine-resistant pancreatic cancer cell models (SW-1990-GR and BxPC3-GR) and one patient-derived xenograft (PDX2846-GR) by successive exposure to increasing doses of gemcitabine. We showed that expression of EGFR, HER2 and HER3 was increased in these gemcitabineresistant pancreatic cancer models, and that an antibody mixture against all three receptors inhibited tumor growth in mice and downregulated HER receptors. Finally, we demonstrated that the Pan-HER and gemcitabine combination has an additive effect in vitro and in mice xenografted with the gemcitabinesensitive or resistant pancreatic models. The mixture of anti-EGFR, HER2 and HER3 antibodies is a good candidate therapeutic approach for gemcitabine-sensitive and -resistant pancreatic cancer.