Menée à l'aide de xénogreffes, cette étude montre que, dans un même échantillon sanguin prélevé sur un patient atteint d'une leucémie myéloïde aiguë, des populations leucémiques sous-clonales peuvent être dotées de propriétés fonctionnelles différentes

Functional Heterogeneity of Genetically Defined Subclones in Acute Myeloid Leukemia

Klco, Jeffery M ; Spencer, David H ; Miller, Christopher A ; Griffith, Malachi ; Lamprecht, Tamara L ; O Laughlin, Michelle ; Fronick, Catrina ; Magrini, Vincent ; Demeter, Ryan T ; Fulton, Robert S ; Eades, William C ; Link, Daniel C ; Graubert, Timothy A ; Walter, Matthew J ; Mardis, Elaine R ; DiPersio, John F ; Wilson, Richard K ; Ley, Timothy J

The relationships between clonal architecture and functional heterogeneity in acute myeloid leukemia (AML) samples are not yet clear. We used targeted sequencing to track AML subclones identified by whole-genome sequencing using a variety of experimental approaches. We found that virtually all AML subclones trafficked from the marrow to the peripheral blood, but some were enriched in specific cell populations. Subclones showed variable engraftment potential in immunodeficient mice. Xenografts [...]

Menée sur des lignées cellulaires de lymphome de Burkitt, puis sur des données portant sur 221 patients, cette étude identifie un caryotype commun à toutes les lignées cellulaires et met en évidence un ensemble de modifications chromosomiques secondaires présentes à la fois dans les lignées cellulaires et les échantillons prélevés sur les patients

Comprehensive cytogenetic and molecular cytogenetic analysis of 44 Burkitt lymphoma cell lines: Secondary chromosomal changes characterization, karyotypic evolution, and comparison with primary samples

Maria Murga Penas, Eva ; Schilling, Georgia ; Behrmann, Petra ; Klokow, Marianne ; Vettorazzi, Eik ; Bokemeyer, Carsten ; Dierlamm, Judith

Burkitt lymphoma cell lines (BL-CL) are used extensively as in vitro models in genetic studies; however, cytogenetic information is not always available or updated. We provide a comprehensive cytogenetic resource of 44 BL-CL, assessed by G-banding, multicolor-FISH, and FISH with 1q, 3p, 7q, and 13q region-specific probes, including the first cytogenetic characterization of 22 BL-CL and the revision of further 22 commonly used BL-CL. Based on these data, we determined a consensus karyotype, [...]

Menée sur des échantillons tumoraux prélevés sur 43 patientes atteintes d'un cancer du sein métastatique (36 échantillons de tumeur primitive, 38 échantillons de tumeur récidivante ou de métastase), cette étude analyse le degré de concordance des anomalies génomiques d'intérêt clinique entre les tumeurs primitives et les tumeurs récidivantes

Concordance of Genomic Alterations Between Primary and Recurrent Breast Cancer

Meric-Bernstam, Funda ; Frampton, Garrett M. ; Ferrer-Lozano, Jaime ; Yelensky, Roman ; Pérez-Fidalgo, José A. ; Wang, Ying ; Palmer, Gary A ; Ross, Jeffrey S ; Miller, Vincent A ; Su, Xiaoping ; Eroles, Pilar ; Barrera, Juan Antonio ; Burgues, Octavio ; Lluch, Ana M. ; Zheng, Xiaofeng ; Sahin, Aysegul A. ; Stephens, Philip J ; Mills, Gordon B. ; Cronin, Maureen T ; Gonzalez-Angulo, Ana M

There is growing interest in delivering genomically-informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next generation sequencing was performed on formalin-fixed paraffin embedded (FFPE) samples, profiling 3320 exons of 182 cancer- related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy number alterations and select rearrangements were assessed in 74 tumors [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une phospholipidase (

Tumor suppressor role of phospholipase Cε in Ras-triggered cancers

Martins, Marta ; McCarthy, Afshan ; Baxendale, Rhona ; Guichard, Sabrina ; Magno, Lorenza ; Kessaris, Nicoletta ; El-Bahrawy, Mona ; Yu, Philipp ; Katan, Matilda

Phospholipase C

Cet article passe en revue les travaux récents sur la signalisation Notch qui, dans les néoplasies lymphoïdes, joue un rôle d'oncogène et, dans les néoplasies myéloïdes, un rôle de suppresseur de tumeurs

Notch signaling: switching an oncogene to a tumor suppressor

Lobry, Camille ; Oh, Philmo ; Mansour, Marc R. ; Look, A. Thomas ; Aifantis, Iannis

The Notch signaling pathway is a regulator of self renewal and differentiation in several tissues and cell types. Notch is a binary cell fate determinant and its hyper-activation has been implicated as oncogenic in several cancers including breast cancer and T-cell acute lymphoblastic leukemia. Recently several studies also unraveled tumor suppressor roles for Notch signaling in different tissues, including tissues where it was before recognized as an oncogene in specific lineages. Whereas [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme de phosphorylation permettant de rendre compte du rôle joué par une hyperactivation de Akt dans les cancers

Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus

Liu, Pengda ; Begley, Michael ; Michowski, Wojciech ; Inuzuka, Hiroyuki ; Ginzberg, Miriam ; Gao, Daming ; Tsou, Peiling ; Gan, Wenjian ; Papa, Antonella ; Kim, Byeong Mo ; Wan, Lixin ; Singh, Amrik ; Zhai, Bo ; Yuan, Min ; Wang, Zhiwei ; Gygi, Steven P. ; Lee, Tae Ho ; Lu, Kun-Ping ; Toker, Alex ; Pandolfi, Pier Paolo ; Asara, John M. ; Kirschner, Marc W. ; Sicinski, Piotr ; Cantley, Lewis ; Wei, Wenyi

Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 and T308 activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel un long ARN non codant (CARLo-5), situé sur la région chromosomique 8q24, favorise le développement d'une tumeur

Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5

Kim, Taewan ; Cui, Ri ; Jeon, Young-Jun ; Lee, Ji-Hoon ; Lee, Ju Hee ; Sim, Hosung ; Park, Jong Kook ; Fadda, Paolo ; Tili, Esmerina ; Nakanishi, Hiroshi ; Huh, Man-Il ; Kim, Sung-Hak ; Cho, Ju Hwan ; Sung, Bong Hwan ; Peng, Yong ; Lee, Tae Jin ; Luo, Zhenghua ; Sun, Hui-Lung ; Wei, Huijun ; Alder, Hansjuerg ; Oh, Jeong Su ; Shim, Kang Sup ; Ko, Sang-Bong ; Croce, Carlo M.

The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found [...]

Menée sur des lignées cellulaires, cette étude identifie un ensemble de voies de signalisation liées à des oncogènes ou suppresseurs de tumeurs et impliquées dans la régulation de l'expression de longs ARNs non codants

Cell cycle, oncogenic and tumor suppressor pathways regulate numerous long and macro non-protein coding RNAs

Hackermuller, Jorg ; Reiche, Kristin ; Otto, Christian ; Hosler, Nadine ; Blumert, Conny ; Brocke-Heidrich, Katja ; Bohlig, Levin ; Nitsche, Anne ; Kasack, Katharina ; Ahnert, Peter ; Krupp, Wolfgang ; Engeland, Kurt ; Stadler, Peter ; Horn, Friedemann

BACKGROUND:The genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein coding RNAs. Despite increasing numbers of functional reports of individual long noncoding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms [...]

Menée à l'aide de poissons zèbres transgéniques, cette étude met en évidence des mécanismes par lesquels, via l'activation de la signalisation Akt, certaines populations clonales de leucémie lymphoblastique aiguë T acquièrent spontanément, en l'absence d'une pression de sélection induite par un traitement, des caractéristiques de cellules souches et de résistance à une chimiothérapie

Clonal Evolution Enhances Leukemia-Propagating Cell Frequency in T Cell Acute Lymphoblastic Leukemia through Akt/mTORC1 Pathway Activation

Blackburn, Jessica S ; Liu, Sali ; Wilder, Jayme L ; Dobrinski, Kimberly P ; Lobbardi, Riadh ; Moore, Finola E ; Martinez, Sarah A ; Chen, Eleanor Y ; Lee, Charles ; Langenau, David M

Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia-propagating potential with time. Akt pathway activation was acquired in a subset of these evolved clones, [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur 60 patients atteints d'un astrocytome, cette étude met en évidence des mécanismes par lesquels, en réduisant au silence le gène suppresseur de tumeurs ST7, la méthyltransférase PRMT5 favorise le développement d'un glioblastome

Genetic Validation of the Protein Arginine Methyltransferase PRMT5 as a Candidate Therapeutic Target in Glioblastoma

Yan, Fengting ; Alinari, Lapo ; Lustberg, Mark E. ; Katherine Martin, Ludmila ; Cordero-Nieves, Hector M. ; Banasavadi-Siddegowda, Yeshavanth ; Virk, Selene ; Barnholtz-Sloan, Jill ; Bell, Erica Hlavin ; Wojton, Jeffrey ; Jacob, Naduparambil K. ; Chakravarti, Arnab ; Nowicki, Michal O. ; Wu, Xin ; Lapalombella, Rosa ; Datta, Jharna ; Yu, Bo ; Gordon, Kate ; Haseley, Amy ; Patton, John T. ; Smith, Porsha L. ; Ryu, John ; Zhang, Xiaoli ; Mo, Xiaokui ; Marcucci, Guido ; Nuovo, Gerard ; Kwon, Chang-Hyuk ; Byrd, John C. ; Chiocca, E. Antonio ; Li, Chenglong ; Sif, Said ; Jacob, Samson ; Lawler, Sean ; Kaur, Balveen ; Baiocchi, Robert A.

Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with [...]

Menée à l'aide de modèles murins, cette étude identifie une surexpression du gène FoxR2 dans un sous-type de médulloblastome caractérisé par l'activation de la signalisation Sonic Hedgehog

Identification of FoxR2 as an oncogene in medulloblastoma

Koso, Hideto ; Tsuhako, Asano ; Lyons, Eli ; Ward, Jerrold M. ; Rust, Alistair G. ; Adams, David J. ; Jenkins, Nancy A. ; Copeland, Neil G. ; Watanabe, Sumiko

Medulloblastoma (MB) is the most common pediatric brain tumor, and in ~25% of cases it is driven by aberrant activation of the Sonic Hedgehog (SHH) pathway in granule neuron precursor cells (GNPs). In this study, we identified novel MB driver genes through a transposon mutagenesis screen in the developing brain of wild-type and Trp53 mutant mice. Twenty-six candidates were identified along with established driver genes such as Gli1 and Crebbp. The transcription factor FoxR2, the most frequent [...]

Menée in vivo, cette étude met en évidence des mécanismes par lesquels l'interleukine 32 favorise la formation de métastases pulmonaires d'un cancer de l'estomac

Interleukin 32 Increases Human Gastric Cancer cell invasion Associated with Tumor Progression and Metastasis

Tsai, Chung-Ying ; Wang, Chia-Siu ; Tsai, Ming-Ming ; Chi, Hsiang-Cheng ; Cheng, Wan-Li ; Tseng, Yi-Hsin ; Chen, Cheng-Yi ; Lin, Crystal D. ; Wu, Jun-Yi ; Wang, Lu-Hai ; Lin, Kwang-Huei

Purpose:The pro-inflammatory cytokine, interleukin 32 (IL-32), is a novel tumor marker highly expressed in various human carcinomas, including gastric cancer (GC). However, its effects on prognosis of GC patients and cancer metastasis are virtually unknown at present. The main aim of the current study was to explore the clinical significance of IL-32 in GC and further elucidate the molecular mechanisms underlying IL-32-mediated migration and invasion. Experimental Design:GC cells with ectopic [...]

Cet article passe en revue les travaux récents sur la biologie des cellules souches métastatiques

Metastatic Stem Cells: Sources, Niches, and Vital Pathways

Oskarsson, Thordur ; Batlle, Eduard ; Massagué, Joan

Metastasis is powered by disseminated cancer cells that re-create a full-fledged tumor in unwelcoming tissues, away from the primary site. How cancer cells moving from a tumor into the circulation manage to infiltrate distant organs and initiate metastatic growth is of interest to cancer biologists and clinical oncologists alike. Recent findings have started to define the sources, phenotypic properties, hosting niches, and signaling pathways that support the survival, self-renewal, dormancy, [...]

Menée sur des échantillons tumoraux prélevés sur 79 patients atteints d'un adénocarcinome canalaire du pancréas, puis in vitro, cette étude met en évidence des mécanismes par lesquels, en activant l'expression de la fascine, HIF-1 favorise les processus invasif et métastatique

HIF-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin

Zhao, Xiao ; Gao, Song ; Ren, He ; Sun, Wei ; Zhang, Huan ; Sun, Jianwei ; Yang, Shengyu ; Hao, Jihui

Early onset of invasive and metastatic progression of pancreatic ductal adenocarcinoma (PDAC) makes it one of the most lethal human cancers. In this study, we investigated the role of the pro-metastatic actin bundling protein fascin in PDAC progression. Expression levels of fascin were higher in cancer tissues than in normal tissues and fascin overexpression correlated with PDAC differentiation and prognosis. Fascin overexpression promoted PDAC cells migration and invasion by elevating MMP-2 [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par des cellules souches cancéreuses exprimant une isoforme de CD44 (CD44v6) dans le processus métastatique d'un cancer colorectal

CD44v6 Is a Marker of Constitutive and Reprogrammed Cancer Stem Cells Driving Colon Cancer Metastasis

Todaro, Matilde ; Gaggianesi, Miriam ; Catalano, Veronica ; Benfante, Antonina ; Iovino, Flora ; Biffoni, Mauro ; Apuzzo, Tiziana ; Sperduti, Isabella ; Volpe, Silvia ; Cocorullo, Gianfranco ; Gulotta, Gaspare ; Dieli, Francesco ; De Maria, Ruggero ; Stassi, Giorgio

Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1± (SDF-1), secreted from tumor associated cells, [...]

Menée sur des cellules tumorales circulantes isolées dans des échantillons sanguins prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence des différences entre les mutations de gènes importants (KRAS, TP53,...) observées dans ces cellules et dans les tumeurs primitives

Immune Escape and Survival Mechanisms in Circulating Tumor Cells of Colorectal Cancer

Steinert, Gunnar ; Schölch, Sebastian ; Niemietz, Thomas ; Iwata, Naoki ; García, Sebastián A. ; Behrens, Bianca ; Voigt, Anita ; Kloor, Matthias ; Benner, Axel ; Bork, Ulrich ; Rahbari, Nuh N. ; Büchler, Markus W. ; Stoecklein, Nikolas H. ; Weitz, Jurgen ; Koch, Moritz

The prognosis of colorectal cancer is closely linked to the occurrence of distant metastases. Systemic dissemination is most likely caused by circulating tumor cells (CTC). Despite the fundamental role of CTC within the metastatic cascade, technical obstacles have so far prevented detailed genomic and, in particular, phenotypic analyses of CTC, which may provide molecular targets to delay or prevent distant metastases. We show here a detailed genomic analysis of single colorectal cancer–derived [...]

Menée in vitro et à partir de données issues du projet "The Cancer Genome Atlas", cette étude identifie une surexpression d'un récepteur couplé aux protéines G (GPR161) dans les cancers du sein triplement négatifs, puis met en évidence son rôle dans le processus invasif

G-protein–coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion

Feigin, Michael E. ; Xue, Bin ; Hammell, Molly C. ; Muthuswamy, Senthil K.

Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer in women and lacks an effective targeted therapy. Therefore, finding common vulnerabilities in these tumors represents an opportunity for more effective treatment. Despite the growing appreciation of G-protein–coupled receptor (GPCR)-mediated signaling in cancer pathogenesis, very little is known about the role GPCRs play in TNBC. Using genomic information of human breast cancer, we have discovered that the orphan GPCR, [...]

Menée à l'aide d'un modèle murin de gliome, cette étude met en évidence des mécanismes par lesquels, en s'exprimant dans la niche périvasculaire de la tumeur, l'ostéopontine active la signalisation CD44, ce qui favorise la prolifération des cellules souches de gliomes ainsi que la résistance à une radiothérapie

Osteopontin-CD44 Signaling in the Glioma Perivascular Niche Enhances Cancer Stem Cell Phenotypes and Promotes Aggressive Tumor Growth

Pietras, Alexander ; Katz, Amanda M ; Ekström, Elin J ; Wee, Boyoung ; Halliday, John J ; Pitter, Kenneth L ; Werbeck, Jillian L ; Amankulor, Nduka M ; Huse, Jason T ; Holland, Eric C

Stem-like glioma cells reside within a perivascular niche and display hallmark radiation resistance. An understanding of the mechanisms underlying these properties will be vital for the development of effective therapies. Here, we show that the stem cell marker CD44 promotes cancer stem cell phenotypes and radiation resistance. In a mouse model of glioma, Cd44−/− and Cd44+/− animals showed improved survival compared to controls. The CD44 ligand osteopontin shared a perivascular expression [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via les récepteurs CXCL8, les macrophages associés aux tumeurs favorisent le processus métastatique d'un carcinome papillaire de la thyroïde

Tumor-associated Macrophages Promote the Metastatic Potential of Thyroid Papillary Cancer by Releasing CXCL8

Fang, Weiyuan ; Ye, Lei ; Shen, Liyun ; Cai, Jie ; Huang, Fengjiao ; Wei, Qing ; Fei, Xiaochun ; Chen, Xi ; Guan, Haixia ; Wang, Weiqing ; Li, Xiaoying ; Ning, Guang

Tumor-associated macrophages (TAMs) can promote cancer initiation and progression by releasing cytokines. Previously, we have found the density of TAMs correlated with lymph node metastasis in papillary thyroid carcinoma (PTC). However the mechanisms of how TAMs promote PTC progression remain unclear.In this study, we first showed that the TAMs density in the tumor core was associated with progressive PTC features and TAMs conditioned medium enhanced PTC cells invasion. Cytokine profiling [...]

Cet article analyse les caractéristiques spécifiques du processus évolutionniste à l'œuvre dans le développement d'une tumeur et, notamment, met en évidence une pression de sélection sur des gènes qui s'expriment dans tous les tissus du corps et n'ont pas encore été associés à la tumorigenèse

Cancer Evolution Is Associated with Pervasive Positive Selection on Globally Expressed Genes

Ostrow, Sheli L. ; Barshir, Ruth ; DeGregori, James ; Yeger-Lotem, Esti ; Hershberg, Ruth

Cancer is an evolutionary process in which cells acquire new transformative, proliferative and metastatic capabilities. A full understanding of cancer requires learning the dynamics of the cancer evolutionary process. We present here a large-scale analysis of the dynamics of this evolutionary process within tumors, with a focus on breast cancer. We show that the cancer evolutionary process differs greatly from organismal (germline) evolution. Organismal evolution is dominated by purifying [...]

Cet article propose une approche permettant d'intégrer les données recueillies sur les cellules souches cancéreuses et sur les génomes de cancer pour une meilleure compréhension de l'hétérogénéité tumorale

Evolution of the Cancer Stem Cell Model

Kreso, Antonija ; Dick, John E

Genetic analyses have shaped much of our understanding of cancer. However, it is becoming increasingly clear that cancer cells display features of normal tissue organization, where cancer stem cells (CSCs) can drive tumor growth. Although often considered as mutually exclusive models to describe tumor heterogeneity, we propose that the genetic and CSC models of cancer can be harmonized by considering the role of genetic diversity and nongenetic influences in contributing to tumor heterogeneity. [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via le micro-ARN miR-21 et le récepteur TLR7, des microvésicules dérivés des tumeurs induisent une apoptose des cellules musculaires

Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7

He, Wei A. ; Calore, Federica ; Londhe, Priya ; Canella, Alessandro ; Guttridge, Denis C. ; Croce, Carlo M.

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression and, in cancers, are often packaged within secreted microvesicles. The cachexia syndrome is a debilitating state of cancer that predominantly results from the loss of skeletal muscle mass, which is in part associated with apoptosis. How tumors promote apoptosis in distally located skeletal muscles has not been explored. Using both tumor cell lines and patient samples, we show that tumor-derived microvesicles induce [...]