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Accueil Nota Bene Cancer V2 Numéro 125 du 28 Février 2012 Biologie

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Nota Bene Cancer Numéro 125 du 28 Février 2012 RSS

Biologie

Aberrations chromosomiques

Menée sur 125 familles finlandaises affectées par le cancer du sein, cette étude (991 cas, 868 témoins) évalue la fréquence de mutations du gène Abraxas, impliqué dans le réseau fonctionnel du gène BRCA1

  • Breast Cancer–Associated Abraxas Mutation Disrupts Nuclear Localization and DNA Damage Response Functions
    Science Translational Medicine, Vol. 4 (122), pp. 122ra23, 2012 (résumé)
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    Menée sur 125 familles finlandaises affectées par le cancer du sein, cette étude (991 cas, 868 témoins) évalue la fréquence de mutations du gène Abraxas, impliqué dans le réseau fonctionnel du gène BRCA1

    “Breast Cancer–Associated Abraxas Mutation Disrupts Nuclear Localization and DNA Damage Response Functions”

    • Solyom, Szilvia;Aressy, Bernadette;Pylkäs, Katri;Patterson-Fortin, Jeffrey;Hartikainen, Jaana M.;Kallioniemi, Anne;Kauppila, Saila;Nikkilä, Jenni;Kosma, Veli-Matti;Mannermaa, Arto;Greenberg, Roger A.;Winqvist, Robert

    Breast cancer is the most common cancer in women in developed countries and has a well-established genetic component. Germline mutations in a network of genes encoding BRCA1, BRCA2, and their interacting partners confer hereditary susceptibility to breast cancer. Abraxas directly interacts with the BRCA1 BRCT (BRCA1 carboxyl-terminal) repeats and contributes to BRCA1-dependent DNA damage responses, making Abraxas a candidate for yet unexplained disease susceptibility. Here, we have screened 125 Northern Finnish breast cancer families for coding region and splice-site Abraxas mutations and genotyped three tagging single-nucleotide polymorphisms within the gene from 991 unselected breast cancer cases and 868 female controls for common cancer-associated variants. A novel heterozygous alteration, c.1082G>A (Arg361Gln), that results in abrogated nuclear localization and DNA response activities was identified in three breast cancer families and in one additional familial case from an ...


Mots clés : Sein; Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée sur un système tridimensionnel de culture cellulaire, cette étude met en évidence un mécanisme par lequel, en induisant l'expression du gène SEMA3F, le gène RORα est susceptible de jouer un rôle de suppresseur de tumeurs dans le cancer du sein

  • RORα suppresses breast tumor invasion through inducing SEMA3F expression
    Cancer Research, sous presse, 2012 (résumé)
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    Menée sur un système tridimensionnel de culture cellulaire, cette étude met en évidence un mécanisme par lequel, en induisant l'expression du gène SEMA3F, le gène RORα est susceptible de jouer un rôle de suppresseur de tumeurs dans le cancer du sein

    “RORα suppresses breast tumor invasion through inducing SEMA3F expression”

    • Xiong, Gaofeng;Wang, Chi;Evers, B. Mark;Zhou, Binhua P.;Xu, Ren

    Inactivation of tumor suppressors and inhibitory microenvironmental factors is necessary for breast cancer invasion; therefore, identifying those suppressors and factors is crucial not only to advancing our knowledge of breast cancer, but also to discovering potential therapeutic targets. By analyzing gene expression profiles of polarized and disorganized human mammary epithelial cells (HMECs) in a physiologically relevant three-dimensional (3D) culture system, we identified retinoid orphan nuclear receptor alpha (RORα) as a transcription regulator of semaphorin 3F (SEMA3F), a suppressive microenvironmental factor. We showed that expression of RORα was down-regulated in human breast cancer tissue and cell lines, and that reduced mRNA levels of RORα and SEMA3F correlated with poor prognosis. Restoring RORα expression reprogrammed breast cancer cells to form non-invasiveness structures in 3D culture and inhibited tumor growth in nude mice, accompanied by enhanced SEMA3F expression. ...


Mots clés : Sein; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'un modèle murin de carcinome mammaire basé sur l'inactivation somatique de p53, cette étude montre que le gène DCC est susceptible de jouer un rôle de suppresseur de tumeurs

  • Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours
    Nature, Vol. 482 (7386), pp. 538-541, 2012 (résumé)
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    Menée à l'aide d'un modèle murin de carcinome mammaire basé sur l'inactivation somatique de p53, cette étude montre que le gène DCC est susceptible de jouer un rôle de suppresseur de tumeurs

    “Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours”

    • Krimpenfort, Paul;Song, Ji-Ying;Proost, Natalie;Zevenhoven, John;Jonkers, Jos;Berns, Anton

    Since its discovery in the early 1990s the deleted in colorectal cancer (DCC) gene, located on chromosome 18q21, has been proposed as a tumour suppressor gene as its loss is implicated in the majority of advanced colorectal and many other cancers. DCC belongs to the family of netrin 1 receptors, which function as dependence receptors as they control survival or apoptosis depending on ligand binding. However, the role of DCC as a tumour suppressor remains controversial because of the rarity of DCC-specific mutations and the presence of other tumour suppressor genes in the same chromosomal region. Here we show that in a mouse model of mammary carcinoma based on somatic inactivation of p53, additional loss of DCC promotes metastasis formation without affecting the primary tumour phenotype. Furthermore, we demonstrate that in cell cultures derived from p53-deficient mouse mammary tumours DCC expression controls netrin-1-dependent cell survival, providing a mechanistic basis for the ...


Mots clés : Sein; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel le micro-ARN 155 joue un rôle d'oncogène dans les liposarcomes

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    Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel le micro-ARN 155 joue un rôle d'oncogène dans les liposarcomes

    “MiR-155 is a liposarcoma oncogene that targets casein kinase-1α and enhances β-catenin signaling”

    • Zhang, Pingyu;Bill, Katelynn;Liu, Juehui;Young, Eric;Peng, Tingsheng;Bolshakov, Svetlana;Hoffman, Aviad;Song, Yechun;Demicco, Elizabeth G;Lopez-Terrada, Dolores;Creighton, Chad J.;Anderson, Matthew L;Lazar, Alexander J.F.;Calin, George;Pollock, Raphael E;Lev, Dina

    Liposarcoma can be an aggressive, debilitating and fatal malignancy. In this study, we identifed microRNAs (miRNAs) associated with the differentiation status of liposarcoma to gain insight into the basis for its progression. miRNA expression profiles determined in human tumors and normal fat specimens identified a de-differentiated tumor expression signature consisting of 35 miRNAs. Deregulated miRNA expression was confirmed in a second independent sample cohort. The miR-155 was the most overexpressed miRNA and functional investigations assigned an important role in the growth of de-differentiated liposarcoma cell lines. Transient or stable knockdown of miR-155 retarded tumor cell growth, decreased colony formation and induced G1-S cell cycle arrest in vitro and blocked tumor growth in murine xenografts in vivo. We identified casein kinase 1α (CK1α) as a direct target of miR-155 control which enhanced β-catenin signaling and cyclin D1 expression, promoting tumor cell growth. In ...


Mots clés : Sarcome; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur des lignées cellulaires de cancer de la prostate, cette étude met en évidence des mécanismes de traduction du génome dépendant de la voie de signalisation mTOR et induisant la formation d'une tumeur ou favorisant le processus métastatique

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    Menée sur des lignées cellulaires de cancer de la prostate, cette étude met en évidence des mécanismes de traduction du génome dépendant de la voie de signalisation mTOR et induisant la formation d'une tumeur ou favorisant le processus métastatique

    “The translational landscape of mTOR signalling steers cancer initiation and metastasis”

    • Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide

    The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our ...


Mots clés : Prostate; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'un modèle murin de trisomie 21, cette étude met en évidence un mécanisme, lié au gène DYRK1A, permettant d'expliquer pourquoi les individus atteints d'une trisomie 21 ont un risque accru de leucémie dans l'enfance et un risque réduit de tumeurs solides à l'âge adulte

  • Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome
    The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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    Menée à l'aide d'un modèle murin de trisomie 21, cette étude met en évidence un mécanisme, lié au gène DYRK1A, permettant d'expliquer pourquoi les individus atteints d'une trisomie 21 ont un risque accru de leucémie dans l'enfance et un risque réduit de tumeurs solides à l'âge adulte

    “Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome”

    • Malinge, Sébastien;Bliss-Moreau, Meghan;Kirsammer, Gina;Diebold, Lauren;Chlon, Timothy;Gurbuxani, Sandeep;Crispino, John D.

    Individuals with Down syndrome (DS; also known as trisomy 21) have a markedly increased risk of leukemia in childhood but a decreased risk of solid tumors in adulthood. Acquired mutations in the transcription factor–encoding GATA1 gene are observed in nearly all individuals with DS who are born with transient myeloproliferative disorder (TMD), a clonal preleukemia, and/or who develop acute megakaryoblastic leukemia (AMKL). Individuals who do not have DS but bear germline GATA1 mutations analogous to those detected in individuals with TMD and DS-AMKL are not predisposed to leukemia. To better understand the functional contribution of trisomy 21 to leukemogenesis, we used mouse and human cell models of DS to reproduce the multistep pathogenesis of DS-AMKL and to identify chromosome 21 genes that promote megakaryoblastic leukemia in children with DS. Our results revealed that trisomy for only 33 orthologs of human chromosome 21 (Hsa21) genes was sufficient to cooperate with GATA1 ...


Mots clés : Leucémie; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide de modèles murins de leucémie avec réarrangement du gène MLL, cette étude met en évidence un mécanisme de régulation par lequel le micro-ARN 196b interagit à la fois, de façon simultanée ou séquentielle, avec des oncogènes et des suppresseurs de tumeurs

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    Menée à l'aide de modèles murins de leucémie avec réarrangement du gène MLL, cette étude met en évidence un mécanisme de régulation par lequel le micro-ARN 196b interagit à la fois, de façon simultanée ou séquentielle, avec des oncogènes et des suppresseurs de tumeurs

    “miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia”

    • Li, Zejuan;Huang, Hao;Chen, Ping;He, Miao;Li, Yuanyuan;Arnovitz, Stephen;Jiang, Xi;He, Chunjiang;Hyjek, Elizabeth;Zhang, Jun;Zhang, Zhiyu;Elkahloun, Abdel;Cao, Donglin;Shen, Chen;Wunderlich, Mark;Wang, Yungui;Neilly, Mary Beth;Jin, Jie;Wei, Minjie;Lu, Jun;Valk, Peter J. M.;Delwel, Ruud;Lowenberg, Bob;Le Beau, Michelle M.;Vardiman, James;Mulloy, James C.;Zeleznik-Le, Nancy J.;Liu, Paul P.;Zhang, Jiwang;Chen, Jianjun

    HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation ...


Mots clés : Leucémie; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur des lignées cellulaires et 82 cas de leucémie aiguë lymphoblastique de type T, cette étude montre que le gène RUNX1 joue un rôle de suppresseur de tumeurs

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    Menée sur des lignées cellulaires et 82 cas de leucémie aiguë lymphoblastique de type T, cette étude montre que le gène RUNX1 joue un rôle de suppresseur de tumeurs

    “Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL”

    • Della Gatta, Giusy;Palomero, Teresa;Perez-Garcia, Arianne;Ambesi-Impiombato, Alberto;Bansal, Mukesh;Carpenter, Zachary W.;De Keersmaecker, Kim;Sole, Xavier;Xu, Luyao;Paietta, Elisabeth;Racevskis, Janis;Wiernik, Peter H.;Rowe, Jacob M.;Meijerink, Jules P.;Califano, Andrea;Ferrando, Adolfo A.

    The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation. Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human ...


Mots clés : Leucémie; Biologie (Oncogènes et suppresseurs de tumeurs)

Progression et métastases

Menée à l'aide d'un modèle murin de cancer de la prostate, cette étude montre que la perte du gène PTEN et l'activation de la signalisation PI33K/AKT induisent ensemble une transition épithélio-mésenchymateuse et favorisent le processus métastatique

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    Menée à l'aide d'un modèle murin de cancer de la prostate, cette étude montre que la perte du gène PTEN et l'activation de la signalisation PI33K/AKT induisent ensemble une transition épithélio-mésenchymateuse et favorisent le processus métastatique

    “Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells”

    • Mulholland, David J.;Kobayashi, Naoko;Ruscetti, Marcus;Zhi, Allen;Tran, Linh M.;Huang, Jiaoti;Gleave, Martin;Wu, Hong

    PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated both in primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-rasG12D/WT mice with the prostate conditional Pten deletion model. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penetrance. A novel stem/progenitor subpopulation with mesenchymal characteristics was ...


Mots clés : Prostate; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur le rôle des exosomes tumoraux dans des mécanismes immunosuppresseurs et la progression d'un cancer

  • Recent advances on the role of tumor exosomes in immunosuppression and disease progression
    Seminars in Cancer Biology, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur le rôle des exosomes tumoraux dans des mécanismes immunosuppresseurs et la progression d'un cancer

    “Recent advances on the role of tumor exosomes in immunosuppression and disease progression”

    • Filipazzi, Paola;Bürdek, Maja;Villa, Antonello;Rivoltini, Licia;Huber, Veronica

    Exosomes are endosomal-derived nanovesicles released by most cells types, including tumor cells, and principally involved in intercellular communication in physiology and disease. Tumor exosomes are gaining increasing interest in medicine and oncology as efficient tools for the delivery of defined signals. Representing the acellular replicas of tumor cells, they contain a great variety of bioactive molecules, such as proteins, RNA, miRNA and DNA. Their great ability to recirculate in body fluids and their structure allow them to transport their cargo to distant targets. Major studies have shown that tumor exosomes convey information not only between tumor cells but also to other cell types, including different immune cell components. There is increasing evidence that these nanovesicles may contribute to cancer progression by influencing different immune cell types, likely blunting specific T cell immunity and skewing innate immune cells toward a pro-tumorigenic phenotype. Because of ...


Mots clés : Cancer (général); Biologie (Progression et métastases)

Ressources et infrastructures (Biologie)

Cet article passe en revue les travaux récents sur la modélisation mathématique de la dynamique cellulaire des leucémies myéloïdes chroniques et évalue leur pertinence à l'aune des recherches en radiobiologie

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    Cet article passe en revue les travaux récents sur la modélisation mathématique de la dynamique cellulaire des leucémies myéloïdes chroniques et évalue leur pertinence à l'aune des recherches en radiobiologie

    “Quantitative modeling of chronic myeloid leukemia: insights from radiobiology”

    • Radivoyevitch, Tomas;Hlatky, Lynn;Landaw, Julian;Sachs, Rainer K

    Mathematical models of chronic myeloid leukemia (CML) cell population dynamics are being developed to improve CML understanding and treatment. We review such models in light of relevant findings from radiobiology, emphasizing three points. First, the CML models almost all assert that the latency time, from CML initiation to diagnosis, is at most ~10 years. Meanwhile, current radiobiological estimates, based on Japanese atomic-bomb survivor data, indicate a substantially higher maximum, suggesting longer-term relapses and suggesting extra resistance mutations. Second, different CML models assume different numbers, between 400 and 106, of normal hematopoietic stem cells (HSC). Radiobiological estimates favor values > 106 for the number of normal cells (often assumed to be the HSC) that are at risk for a CML-initiating BCR-ABL translocation. Moreover there is some evidence for an HSC dead-band hypothesis, consistent with HSC numbers being very different across different healthy adults. ...


Mots clés : Leucémie; Biologie (Ressources et infrastructures (Biologie))

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