A partir d'échantillons prélevés sur 62 patients atteints d'une leucémie/lymphome à cellules T de l'adulte (27 de type chronique, 35 de type aigu), cette étude japonaise identifie un ensemble d'anomalies génomiques associées à la transformation d'une maladie de type chronique en type aigu

Molecular Characterization of Chronic-type Adult T-cell Leukemia/Lymphoma

Yoshida, Noriaki ; Karube, Kennosuke ; Utsunomiya, Atae ; Tsukasaki, Kunihiro ; Imaizumi, Yoshitaka ; Taira, Naoya ; Uike, Naokuni ; Umino, Akira ; Arita, Kotaro ; Suguro, Miyuki ; Tsuzuki, Shinobu ; Kinoshita, Tomohiro ; Ohshima, Koichi ; Seto, Masao

Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1–induced neoplasm with four clinical subtypes: acute, lymphoma, chronic, and smoldering. Although the chronic type is regarded as indolent ATL, about half of the cases progress to acute-type ATL. The molecular pathogenesis of acute transformation in chronic-type ATL is only partially understood. In an effort to determine the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation, [...]

A partir de données du projet "The Cancer Genome Atlas" portant sur 2 728 participants, cette étude identifie, dans les cellules sanguines, un ensemble de mutations dans des gènes associés aux lymphomes et/ou aux leucémies, notamment chez les patients les plus âgés

Age-related mutations associated with clonal hematopoietic expansion and malignancies

Xie, Mingchao ; Lu, Charles ; Wang, Jiayin ; McLellan, Michael D. ; Johnson, Kimberly J. ; Wendl, Michael C. ; McMichael, Joshua F. ; Schmidt, Heather K. ; Yellapantula, Venkata ; Miller, Christopher A. ; Ozenberger, Bradley A. ; Welch, John S. ; Link, Daniel C. ; Walter, Matthew J. ; Mardis, Elaine R. ; DiPersio, John F. ; Chen, Feng ; Wilson, Richard K. ; Ley, Timothy J. ; Ding, Li

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in [...]

Menée à l'aide d'un modèle murin de cancer du poumon, cette étude évalue l'intérêt d'une technique d'édition du génome pour caractériser les conséquences fonctionnelles des mutations somatiques identifiées dans les études de séquençage du génome des cancers

Rapid modelling of cooperating genetic events in cancer through somatic genome editing

Sanchez-Rivera, Francisco J. ; Papagiannakopoulos, Thales ; Romero, Rodrigo ; Tammela, Tuomas ; Bauer, Matthew R. ; Bhutkar, Arjun ; Joshi, Nikhil S. ; Subbaraj, Lakshmipriya ; Bronson, Roderick T. ; Xue, Wen ; Jacks, Tyler

Cancer is a multistep process that involves mutations and other alterations in oncogenes and tumour suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Here we describe a novel CRISPR/Cas9-based approach for rapid functional investigation of candidate genes in well-established autochthonous mouse models of [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels plusieurs voies de signalisation (FGF, Wnt, TGF-

The Tumor Suppressor Smad4/DPC4 Is Regulated by Phosphorylations that Integrate FGF, Wnt, and TGF-β Signaling

Demagny, Hadrien ; Araki, Tatsuya ; De Robertis, Edward M

Smad4 is a major tumor suppressor currently thought to function constitutively in the transforming growth factor

Cet article passe en revue les travaux récents sur le rôle du gène MICA et de ses polymorphismes dans les cancers

MICA polymorphism: biology and importance in cancer

Chen, Dan ; Gyllensten, Ulf

The major histocompatibility complex (MHC) class I polypeptide-related sequence A gene (MICA) encodes a membrane-bound protein acting as a ligand to stimulate an activating receptor, NKG2D, expressed on the surface of essentially all human natural killer (NK), γδ T, and CD8+ αβ T cells. MICA protein is absent from most cells but can be induced by infections and oncogenic transformation, and is frequently expressed in epithelial tumors. Upon binding to MICA, NKG2D activates cytolytic responses [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une déméthylase (UTX) exerce une fonction de suppresseur de tumeurs dans les leucémies lymphoblastiques aiguës T affectant des patients masculins

The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia

Van der Meulen, Joni ; Sanghvi, Viraj ; Mavrakis, Konstantinos ; Durinck, Kaat ; Fang, Fang ; Matthijssens, Filip ; Rondou, Pieter ; Vandenberghe, Peter ; Delabesse, Eric ; Lammens, Tim ; De Moerloose, Barbara ; Menten, Björn ; Van Roy, Nadine ; Verhasselt, Bruno ; Poppe, Bruce ; Benoit, Yves ; Taghon, Tom ; Melnick, Ari ; Speleman, Frank ; Wendel, Hans-Guido ; Van Vlierberghe, Pieter

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia that is mainly diagnosed in children and shows a skewed gender distribution towards males. Here, we report somatic loss-of-function mutations in the X-linked histone H3K27me3 demethylase UTX in human T-ALL. Interestingly, UTX mutations were exclusively present in male T-ALL patients and allelic expression analysis revealed that UTX escapes X-inactivation in female T-ALL lymphoblasts and normal T-cells. Notably, we [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en régulant de façon négative l'expression du gène p53, le facteur inhibiteur de la leucémie LIF favorise la progression d'un cancer colorectal et la résistance thérapeutique

LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers

Yu, Haiyang ; Yue, Xuetian ; Zhao, Yuhan ; Li, Xiaoyan ; Wu, Lihua ; Zhang, Cen ; Liu, Zhen ; Lin, Kevin ; Xu-Monette, Zijun Y. ; Young, Ken H. ; Liu, Juan ; Shen, Zhiyuan ; Feng, Zhaohui ; Hu, Wenwei

Leukaemia inhibitory factor (LIF) has been recently identified as a p53 target gene, which mediates the role of p53 in maternal implantation under normal physiological conditions. Here we report that LIF is a negative regulator of p53; LIF downregulates p53 protein levels and function in human colorectal cancer (CRC) cells. The downregulation of p53 by LIF is mediated by the activation of Stat3, which transcriptionally induces inhibitor of DNA-binding 1 (ID1). ID1 upregulates MDM2, a key [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la perte combinée de l'expression des gènes suppresseurs de tumeurs Pten et p53 favorise le développement d'un cancer du sein triplement négatif

Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K

Liu, Jeff C. ; Voisin, Veronique ; Wang, Sharon ; Wang, Dong-Yu ; Jones, Robert A. ; Datti, Alessandro ; Uehling, David ; Al-awar, Rima ; Egan, Sean E. ; Bader, Gary D. ; Tsao, Ming ; Mak, Tak W. ; Zacksenhaus, Eldad

The tumor suppressors Pten and p53 are frequently lost in breast cancer, yet the consequences of their combined inactivation are poorly understood. Here, we show that mammary-specific deletion of Pten via WAP-Cre, which targets alveolar progenitors, induced tumors with shortened latency compared to those induced by MMTV-Cre, which targets basal/luminal progenitors. Combined Pten-p53 mutations accelerated formation of claudin-low, triple-negative-like breast cancer (TNBC) that exhibited [...]

Menée à l'aide de modèles murins et d'échantillons tumoraux prélevés sur 16 patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence des mécanismes par lesquels, dans les macrophages associés aux tumeurs, l'expression d'une enzyme, l'héparanase, favorise la prolifération des cellules cancéreuses

Macrophage Polarization in Pancreatic Carcinoma: Role of Heparanase Enzyme

Hermano, Esther ; Meirovitz, Amichay ; Meir, Karen ; Nussbaum, Gabriel ; Appelbaum, Limor ; Peretz, Tamar ; Elkin, Michael

Background : Tumor microenvironment, and particularly tumor-associated macrophages (TAMs), represent a key contributing factor in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Here we report that heparanase (predominant enzyme degrading heparan sulfate, the main polysaccharide found at the cell surface and extracellular matrix) directs tumor-promoting behavior of TAM in PDAC. Methods : A mouse model of heparanase-overexpressing pancreatic carcinoma (n = 5 mice/group), tumor-associated [...]

Menée in vitro, in vivo et à partir de données portant sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer métastatique du sein, cette étude met en évidence des mécanismes par lesquels, via la régulation de l'expression du gène FOXP2, le micro-ARN 199a favorise le processus métastatique

MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis

Cuiffo, Benjamin G ; Campagne, Antoine ; Bell, George W ; Lembo, Antonio ; Orso, Francesca ; Lien, Evan C ; Bhasin, Manoj K ; Raimo, Monica ; Hanson, Summer E ; Marusyk, Andriy ; El-Ashry, Dorraya ; Hematti, Peiman ; Polyak, Kornelia ; Mechta-Grigoriou, Fatima ; Mariani, Odette ; Volinia, Stefano ; Vincent-Salomon, Anne ; Taverna, Daniela ; Karnoub, Antoine E

Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate [...]

Menée à l'aide de modèles murins de gliome, cette étude met en évidence des mécanismes par lesquels l'angiogenèse est favorisée par l'expression du gène RAGE dans les macrophages associés aux tumeurs

RAGE Expression in Tumor-associated Macrophages Promotes Angiogenesis in Glioma

Chen, Xuebo ; Zhang, Leying ; Zhang, Ian Y ; Liang, Junling ; Wang, Huaqing ; Ouyang, Mao ; Wu, Shihua ; Carvalho da Fonseca, Anna ; Weng, Lihong ; Yamamoto, Yasuhiko ; Yamamoto, Hiroshi ; Natarajan, Rama ; Badie, Behnam

Interaction of RAGE with its ligands can promote tumor progression, invasion and angiogenesis. Although blocking RAGE signaling has been proposed as a potential anti-cancer strategy, functional contributions of RAGE expression in the tumor microenvironment (TME) has not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and non-invasive glioma models, animal survival was prolonged in RAGE knockout (Ager-/-) [...]

Cett article présente les caractéristiques d'un nouveau modèle murin génétiquement modifié pour l'étude de l'évolution d'une tumeur du pancréas et de la résistance thérapeutique

A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer

Schonhuber, Nina ; Seidler, Barbara ; Schuck, Kathleen ; Veltkamp, Christian ; Schachtler, Christina ; Zukowska, Magdalena ; Eser, Stefan ; Feyerabend, Thorsten B. ; Paul, Mariel C. ; Eser, Philipp ; Klein, Sabine ; Lowy, Andrew M. ; Banerjee, Ruby ; Yang, Fangtang ; Lee, Chang-Lung ; Moding, Everett J. ; Kirsch, David G. ; Scheideler, Angelika ; Alessi, Dario R. ; Varela, Ignacio ; Bradley, Allan ; Kind, Alexander ; Schnieke, Angelika E. ; Rodewald, Hans-Reimer ; Rad, Roland ; Schmid, Roland M. ; Schneider, Günter ; Saur, Dieter

Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep [...]

Cet article passe en revue les travaux récents sur les mécanismes de régression spontanée d'un neuroblastome

Mechanisms of neuroblastoma regression

Brodeur, Garrett M. ; Bagatell, Rochelle

Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, [...]