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Peripheral T cell lymphoma (PTCL) is a heterogeneous group of hematological cancers arising from the malignant transformation of mature T cells. In a cohort of 28 PTCL cases, we identified recurrent overexpression of MYCN, a member of the MYC family of oncogenic transcription factors. Approximately half of all PTCL cases was characterized by a MYC expression signature. Inducible expression of MYCN in lymphoid cells in a mouse model caused T cell lymphoma that recapitulated human PTCL with a MYC expression signature. Integration of mouse and human expression data identified EZH2 as a key downstream target of MYCN. Remarkably, EZH2 was found to be an essential co-factor for the transcriptional activation of the MYCN-driven gene expression program, which was independent of methyltransferase activity, but dependent on phosphorylation by CDK1. MYCN-driven T cell lymphoma was sensitive to EZH2 degradation or CDK1 inhibition, which displayed synergy with FDA-approved HDAC inhibitors.

Colorectal cancer (CRC) is highly prevalent in Western society, and increasing evidence indicates strong contributions of environmental factors and the intestinal microbiota to CRC initiation, progression and even metastasis. We have identified a synergistic inflammatory tumor-promoting mechanism through which the resident intestinal microbiota boosts invasive CRC development in an epithelial-to-mesenchymal transition-prone tissue environment. Intestinal epithelial cell (IEC)-specific transgenic expression of the epithelial-to-mesenchymal transition regulator Zeb2 in mice (Zeb2IEC-Tg/+) leads to increased intestinal permeability, myeloid cell-driven inflammation and spontaneous invasive CRC development. Zeb2IEC-Tg/+ mice develop a dysplastic colonic epithelium, which progresses to severely inflamed neoplastic lesions while the small intestinal epithelium remains normal. Zeb2IEC-Tg/+ mice are characterized by intestinal dysbiosis, and microbiota depletion with broad-spectrum antibiotics or germ-free rederivation completely prevents cancer development. Zeb2IEC-Tg/+ mice represent the first mouse model of spontaneous microbiota-dependent invasive CRC and will help us to better understand host–microbiome interactions driving CRC development in humans.

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Ashenafi Bulle,1 Jeroen Dekervel,1 Lise Deschuttere,1 David Nittner,2,3 Eric Van Cutsem,1 Chris Verslype,1 Jos van Pelt1 1Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven & University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium; 2Histopathology Expertise Center, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium; 3Department of Oncology, KU Leuven, Leuven, BelgiumCorrespondence: Jos van PeltLaboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven & University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, BelgiumTel +32-16-330 694Fax +32-16-330 718Email jos.vanpelt@kuleuven.bePurpose: All currently available therapies for the treatment of pancreatic ductal adenocarcinoma (PDAC) show limited success. PDACs fast progression depends on the tumor characteristics and can be influenced by the microenvironment. The antibacterial drug acriflavine (ACF) has been shown to have anti-cancer activities in cell lines.Materials and Methods: To understand the working mechanism of ACF on cancer progression and tumor-stromal interplay, we evaluated pancreatic cancer in cell culture (Panc-1) (morphology, cell invasion and RNA expression) and the macrophage cell line THP1 (representing innate immune stromal cells). In the translational arm, the activity of ACF on xenograft models of human PDAC tumors representing different clinical subclasses was investigated (tumor growth, morphology and immunofluorescence, RNA expression and pathway analysis).Results: In vitro, ACF reduces epithelial-to-mesenchymal transition (EMT) and invasion of Panc-1 cells and shifts macrophage polarization to a M1-like anti-tumoral phenotype. At non-toxic concentrations, ACF downregulates cell metabolism. In xenografts, effect on tumor growth and metabolism could be confirmed; however, the innate immune stromal cells did not respond. Importantly, only in the moderately differentiated PDAC model, ACF co

There is a lack of well-characterized models for pancreatic ductal adenocarcinoma (PDAC). PDAC itself is unique because of its pronounced tumor microenvironment that influences tumor progression, behavior and therapeutic resistance. Here we investigated, in patient-derived tumor xenograft (PDTX) models developed from fine needle biopsies, the cancer cells behavior, Epithelial-to-Mesenchymal Transition (EMT) and drug response. For this, we studied two behaviorally distinct PDTX models. Tumor volume measurement, histology, immuno-histochemical staining, RT-qPCR, RNA sequencing and Western blotting were used to further characterize these models and investigate the effect of two classes of drugs (gemcitabine and acriflavine (HIF-inhibitor)). The models recapitulated the corresponding primary tumors. The growth-rate of the poorly differentiated tumor (PAC010) was faster than that of the moderately differentiated tumor (PAC006) (P<0.05). The PAC010 model showed increased cell proliferation (Ki-67 staining) and markers indicating survival (increased p-AKT, p-ERK and p-NF-kB65 and suppressin of cleaved PARP). Gene and protein analysis showed higher expression of mesenchymal markers in PAC010 model (e.g. VIM, SNAI2). Pathway analysis demonstrated activation of processes related to EMT, tumor progression and aggressiveness in PAC010. Gemcitabine treatment resulted in shrinking of the tumor volume and reduced proliferation in both models. Importantly, gemcitabine treatment significantly enhanced the expression of mesenchymal marker supportive of metastatic behavior and of survival pathways, particularly in the non-aggressive PAC006 model. Acriflavine had little effect on tumor growth in both models. In conclusion, we observed in this unique model of PDAC, a clear link between EMT and poor tumor differentiation and found that gemcitabine can increase EMT.

Recently, several promising treatments for high-grade gliomas (HGGs) failed to provide significant benefit when translated from the preclinical setting to patients. Improving the animal models is fundamental to overcoming this translational gap. To address this need, we developed and comprehensively characterized a new in vivo model based on the orthotopic implantation of CT-2A cells cultured in neurospheres (NS/CT-2A). Murine CT-2A methylcholanthrene-induced HGG cells (C57BL/6 background) were cultured in monolayers (ML) or NS and orthotopically inoculated in syngeneic animals. ML/CT-2A and NS/CT-2A tumors’ characterization included the analysis of tumor growth, immune microenvironment, glioma stem cells (GSCs), vascularization and metabolites. The immuno-modulating properties of NS/CT-2A and ML/CT-2A cells on splenocytes were tested in vitro. Mice harboring NS/CT-2A tumors had a shorter survival than those harboring ML/CT-2A tumors (P=0.0033). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors showed more abundant GSCs (P=0.0002 and 0.0770 for Nestin and CD133, respectively) and regulatory T cells (Tregs, P=0.0074), and a strong tendency towards an increased vascularization (P=0.0503). There were no significant differences in metabolites’ composition between NS/ and ML/CT-2A tumors. In vitro, NS were able to drive splenocytes towards a more immunosuppressive status by reducing CD8+ T cells (P=0.0354) and by promoting Tregs (P=0.0082), macrophages (MF, P=0.0019) and their M2 subset (P=0.0536). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors show a more aggressive phenotype with increased immunosuppression and GSCs proliferation. Because of these specific features, the NS/CT-2A model represents a clinically relevant platform in the search for new HGG treatments aimed at reducing immunosuppression and eliminating GSCs., SCOPUS: ar.j, info:eu-repo/semantics/published

Although numerous epigenetic aberrancies accumulate in melanoma, their contribution to initiation and progression remain unclear. The epigenetic mark 5-hydroxymethylcyto-sine (5hmC), generated through TET-mediated DNA modification, is now referred to as the sixth base of DNA and has recently been reported as a potential biomarker for multiple types of cancer. Loss of 5hmC is an epigenetic hallmark of melanoma, but whether a decrease in 5hmc levels contributes directly to pathogenesis or whether it merely results from disease progression-associated epigenetic remodeling remains to be established. Here, we show that NRAS-driven melanomagenesis in mice is accompanied by an overall decrease in 5hmC and specific 5hmC gains in selected gene bodies. Strikingly, genetic ablation of Tet2 in mice cooperated with oncogenic NRASQ61K to promote melanoma initiation while suppressing specific gains in 5hmC. We conclude that TET2 acts as a barrier to melanoma initiation and progression, partly by promoting 5hmC gains in specific gene bodies. Significance: This work emphasizes the importance of epigenome plasticity in cancer development and highlights the involvement of druggable epigenetic factors in cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells. This approach may help overcome the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1, 2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis(3-5). We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-17-92 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17-92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published