Menée initialement sur 12 cas de cancer de l'endomètre, puis sur des lignées cellulaires et 222 échantillons tumoraux prélevés sur 222 patientes, cette étude identifie de nouveaux gènes dont les mutations sont associées au développement de ce cancer

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

Liang, Han ; Cheung, Lydia W.T. ; Li, Jie ; Ju, Zhenlin ; Yu, Shuangxing ; Stemke-Hale, Katherine ; Dogruluk, Turgut ; Lu, Yiling ; Liu, Xiuping ; Gu, Chao ; Guo, Wei ; Scherer, Steven E. ; Carter, Hannah ; Westin, Shannon N. ; Dyer, Mary D. ; Verhaak, Roeland G.W. ; Zhang, Fan ; Karchin, Rachel ; Liu, Chang-Gong ; Lu, Karen H. ; Broaddus, Russell R. ; Scott, Kenneth L. ; Hennessy, Bryan T. ; Mills, Gordon B.

Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial [...]

Menée à l'aide d'un modèle murin, cette étude suggère que l'origine d'un cholangiocarcinome intra-hépatique réside dans les hépatocytes, et non les cholangiocytes, en association avec une activation de la signalisation Notch

Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes

Sekiya, Sayaka ; Suzuki, Atsushi

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary malignancy in the liver. ICC has been classified as a malignant tumor arising from cholangiocytes; however, the co-occurrence of ICC and viral hepatitis suggests that ICC originates in hepatocytes. In order to determine the cellular origin of ICC, we used a mouse model of ICC in which hepatocytes and cholangiocytes were labeled with heritable, cell type–specific reporters. Our studies reveal that ICC is generated by biliary [...]

Menée à l'aide de modèles murins génétiquement modifiés, cette étude montre que, au début du développement d'un cancer du foie, la survie des cellules cancéreuses dépend d'une inhibition de l'apoptose par l'intermédiaire d'une répression de l'expression de la survivine

Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin

Min, Lihua ; Ji, Yuan ; Bakiri, Latifa ; Qiu, Zhixin ; Cen, Jin ; Chen, Xiaotao ; Chen, Lingli ; Scheuch, Harald ; Zheng, Hai ; Qin, Lunxiu ; Zatloukal, Kurt ; Hui, Lijian ; Wagner, Erwin F.

Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome de l'œsophage, cette étude met en évidence une fréquente surexpression du facteur de transcription FOXM1 et de son gène cible, PLK1

The FOXM1-PLK1 axis is commonly upregulated in oesophageal adenocarcinoma

Dibb, M. ; Han, N. ; Choudhury, J. ; Hayes, S. ; Valentine, H. ; West, C. ; Ang, Y. S. ; Sharrocks, A. D.

Background: The transcription factor FOXM1 is an important regulator of the cell cycle through controlling periodic gene expression during the G2 and M phases. One key target for FOXM1 is the gene encoding the protein kinase PLK1 and PLK1 itself acts in a positive feedback loop to phosphorylate and activate FOXM1. Both FOXM1 and PLK1 have been shown to be overexpressed in a variety of different tumour types. Methods: We have used a combination of RT–PCR, western blotting, tissue microarrays and [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation du récepteur TLR7 au sein du micro-environnement tumoral favorise la croissance d'un adénocarcinome canalaire du pancréas

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

Ochi, Atsuo ; Graffeo, Christopher S. ; Zambirinis, Constantinos P. ; Rehman, Adeel ; Hackman, Michael ; Fallon, Nina ; Barilla, Rocky M. ; Henning, Justin R. ; Jamal, Mohsin ; Rao, Raghavendra ; Greco, Stephanie ; Deutsch, Michael ; Medina-Zea, Marco V. ; Saeed, Usama Bin ; Ego-Osuala, Melvin O. ; Hajdu, Cristina ; Miller, George

Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and [...]

Menée sur un modèle murin, cette étude met en évidence un mécanisme de nature inflammatoire impliqué dans la croissance d'une tumeur colorectale

Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth

Grivennikov, Sergei I. ; Wang, Kepeng ; Mucida, Daniel ; Stewart, C. Andrew ; Schnabl, Bernd ; Jauch, Dominik ; Taniguchi, Koji ; Yu, Guann-Yi ; Osterreicher, Christoph H. ; Hung, Kenneth E. ; Datz, Christian ; Feng, Ying ; Fearon, Eric R. ; Oukka, Mohamed ; Tessarollo, Lino ; Coppola, Vincenzo ; Yarovinsky, Felix ; Cheroutre, Hilde ; Eckmann, Lars ; Trinchieri, Giorgio ; Karin, Michael

Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of

Menée in vitro et in vivo, cette étude suggère que la protéine GBP-1 joue un rôle de suppresseur de tumeurs dans les carcinomes colorectaux

GBP-1 acts as a tumor suppressor in colorectal cancer cells

Britzen-Laurent, Nathalie ; Lipnik, Karoline ; Ocker, Matthias ; Naschberger, Elisabeth ; Schellerer, Vera S. ; Croner, Roland S. ; Vieth, Michael ; Waldner, Maximilian ; Steinberg, Pablo ; Hohenadl, Christine ; Sturzl, Michael

The human guanylate-binding protein 1 (GBP-1) is among the proteins the most highly induced by IFN-γ in every cell type investigated as yet. In vivo, GBP-1 expression is associated with the presence of inflammation and has been observed in autoimmune diseases, inflammatory bowel diseases (IBD) and cancer. In colorectal carcinoma (CRC), the expression of GBP-1 in the desmoplastic stroma has been previously reported to correlate with the presence of an IFN-γ-dominated Th1 micromilieu and with an [...]

Menée sur des lignées cellulaires, cette étude met en évidence un mécanisme par lequel la protéine GREB1 favorise la prolifération cellulaire dans le cancer du sein

GREB1 Functions as a Growth Promoter and Is Modulated by IL6/STAT3 in Breast Cancer

Liu, Mingli ; Wang, Guangdi ; Gomez-Fernandez, Carmen R. ; Guo, Shanchun

Background: Growth Regulation by Estrogen in Breast cancer (GREB1) was an estrogen receptor (ER) target gene, and GREB1 expression inversely correlated with HER2 status, possibly as a surrogate marker for ER status and a predictor for tamoxifen resistance in breast cancer patients. In the present study, we examine the function and regulation of GREB1 in breast cancer, with the goal to develop GREB1 as a biomarker in breast cancer with de novo and acquired tamoxifen resistance. Methods:We [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant de façon négative l'expression du facteur NF-κB, la protéine 53BP1 exerce un rôle de suppresseur de tumeurs dans le cancer du sein

53BP1 functions as a tumor suppressor in breast cancer via the inhibition of NF-κB through miR-146a

Li, Xiaoyan ; Xu, Bing ; Moran, Meena S. ; Zhao, Yuhan ; Su, Peng ; Haffty, Bruce G. ; Shao, Changshun ; Yang, Qifeng

p53-binding protein-1 (53BP1) plays a critical role in cell cycle checkpoint and DNA repair activities. Recently, 53BP1 was recognized as a potential tumor suppressor gene. In this report, we investigated its tumor suppressor function in breast cancer. In clinical samples, we observed a lower level of 53BP1 expression in the cancer lesions than in the matched non-tumor tissues. Furthermore, the 53BP1 level showed a gradual decrease during the progression from precancerous to cancer lesion. [...]

Menée sur des lignées cellulaires et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en régulant l'expression de la protéine MYCN par l'intermédiaire de la répression de micro-ARNs de la famille let-7, LIN28B favorise le développement d'un neuroblastome

LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

Molenaar, Jan J. ; Domingo-Fernandez, Raquel ; Ebus, Marli E. ; Lindner, Sven ; Koster, Jan ; Drabek, Ksenija ; Mestdagh, Pieter ; van Sluis, Peter ; Valentijn, Linda J. ; van Nes, Johan ; Broekmans, Marloes ; Haneveld, Franciska ; Volckmann, Richard ; Bray, Isabella ; Heukamp, Lukas ; Sprussel, Annika ; Thor, Theresa ; Kieckbusch, Kristina ; Klein-Hitpass, Ludger ; Fischer, Matthias ; Vandesompele, Jo ; Schramm, Alexander ; van Noesel, Max M. ; Varesio, Luigi ; Speleman, Frank ; Eggert, Angelika ; Stallings, Raymond L. ; Caron, Huib N. ; Versteeg, Rogier ; Schulte, Johannes H.

LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs [...]

Menée sur des échantillons tumoraux et des lignées cellulaires, cette étude met en évidence un mécanisme régulant l'expression du proto-oncogène c-Jun dans les glioblastomes

Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation

Blau, Lior ; Knirsh, Revital ; Ben-Dror, Iris ; Oren, Sivan ; Kuphal, Silke ; Hau, Peter ; Proescholdt, Martin ; Bosserhoff, Anja-Katrin ; Vardimon, Lily

Although the protooncogene c-Jun plays a critical role in cell proliferation, cell death, and malignant transformation, DNA microarray screens have identified only a few human cancer types with aberrant expression of c-Jun. Here, we show that c-Jun accumulation is robustly elevated in human glioblastoma and that this increase contributes to the malignant properties of the cells. Most importantly, the increase in c-Jun protein accumulation occurs with no corresponding increase in c-Jun mRNA or [...]

Menée à l'aide d'un modèle murin de lymphome non hodgkinien, cette étude met en évidence, grâce à l'observation d'un ganglion lymphatique périphérique par une technique d'imagerie multimodale, différentes étapes de la progression de la maladie

Unexpected dissemination patterns in lymphoma progression revealed by serial imaging within a murine lymph node

Ito, Ken ; Smith, Bryan Ronain ; Parashurama, Natesh ; Yoon, Joon-Kee ; Song, Si Yeol ; Miething, Cornelius ; Mallick, Parag ; Lowe, Scott W. ; Gambhir, Sanjiv Sam

Non-Hodgkin's lymphoma (NHL) is a heterogeneous and highly disseminated disease, but the mechanisms of its growth and dissemination are not well understood. Using a mouse model of this disease, we employed multimodal imaging, including intravital microscopy (IVM) combined with bioluminescence, as a powerful tool to better elucidate NHL progression. We injected EGFP and luciferase-expressing Eμ-Myc/Arf-/- (Cdkn2a-/-) mouse lymphoma cells (EL-Arf-/-) into C57BL/6NCrl mice intravenously. Long-term [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par une enzyme, la lysyl oxydase, dans le processus métastatique d'un cancer du sein

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

El-Haibi, Christelle P. ; Bell, George W. ; Zhang, Jiangwen ; Collmann, Anthony Y. ; Wood, David ; Scherber, Cally M. ; Csizmadia, Eva ; Mariani, Odette ; Zhu, Cuihua ; Campagne, Antoine ; Toner, Mehmet ; Bhatia, Sangeeta N. ; Irimia, Daniel ; Vincent-Salomon, Anne ; Karnoub, Antoine E.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSC-induced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human [...]