Biologie

A partir du séquençage du génome tumoral d'un patient atteint d'un médulloblastome Sonic-Hedgehog et présentant une mutation germinale du gène TP53, puis du séquençage de divers autres génomes tumoraux, notamment de patients atteints d'une leucémie myéloïde aiguë, cette étude identifie une association entre des mutations du gène p53 et des réarrangements massifs de l'ADN

• Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations
  • Cell, Vol. 148 (1), pp. 59-71, 2012 (résumé)
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  A partir du séquençage du génome tumoral d'un patient atteint d'un médulloblastome Sonic-Hedgehog et présentant une mutation germinale du gène TP53, puis du séquençage de divers autres génomes tumoraux, notamment de patients atteints d'une leucémie myéloïde aiguë, cette étude identifie une association entre des mutations du gène p53 et des réarrangements massifs de l'ADN

  “Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations”

  • Rausch, Tobias;Jones, David T W.;Zapatka, Marc;Stütz, Adrian M;Zichner, Thomas;Weischenfeldt, Joachim;Jäger, Natalie;Remke, Marc;Shih, David;Northcott, Paul A;Pfaff, Elke;Tica, Jelena;Wang, Qi;Massimi, Luca;Witt, Hendrik;Bender, Sebastian;Pleier, Sabrina;Cin, Huriye;Hawkins, Cynthia;Beck, Christian;von Deimling, Andreas;Hans, Volkmar;Brors, Benedikt;Eils, Roland;Scheurlen, Wolfram;Blake, Jonathon;Benes, Vladimir;Kulozik, Andreas E;Witt, Olaf;Martin, Dianna;Zhang, Cindy;Porat, Rinnat;Merino, Diana M.;Wasserman, Jonathan;Jabado, Nada;Fontebasso, Adam;Bullinger, Lars;Rücker, Frank G.;Döhner, Konstanze;Döhner, Hartmut;Koster, Jan;Molenaar, Jan J;Versteeg, Rogier;Kool, Marcel;Tabori, Uri;Malkin, David;Korshunov, Andrey;Taylor, Michael D;Lichter, Peter;Pfister, Stefan M;Korbel, Jan O

  Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings ...

  
  

Mots clés : Système nerveux central; Biologie (Aberrations chromosomiques)

Cet article passe en revue les travaux récents sur l'identification de mutations génomiques dans les mélanomes

• Reviewing the somatic genetics of melanoma: from current to future analytical approaches
  • Pigment Cell & Melanoma Research, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur l'identification de mutations génomiques dans les mélanomes

  “Reviewing the somatic genetics of melanoma: from current to future analytical approaches”

  • Dutton-Regester, Ken;Hayward, Nicholas K.

  Metastatic melanoma has traditionally been difficult to treat and although molecularly based targeted therapies have shown promising results, they have yet to show consistent improvements in overall survival rates. Thus, identifying the key mutation events underlying the etiology of metastatic melanoma will no doubt lead to the improvement of existing therapeutic approaches and the development of new treatment strategies. Significant advances towards understanding the complexity of the melanoma genome have recently been achieved using next generation sequencing technologies. However, identifying those mutations driving tumorigenesis will continue to be a challenge for researchers, in part due to the high rates of mutation compared to other cancers. This article will review the catalog of mutations identified in melanoma through a variety of approaches, including the use of unbiased exome and whole-genome next generation sequencing platforms, as well discuss complementary strategies ...

  
  

Mots clés : Mélanome; Biologie (Aberrations chromosomiques)

Menée sur les génomes tumoraux et non tumoraux de 4 patients atteints d'un carcinome hépatocellulaire, cette étude de séquençage dresse la cartographie des anomalies de l'ADN des cellules tumorales induites par l'intégration du génome du virus de l'hépatite B

• The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients
  • Genome Research, sous presse, 2012 (article en libre accès)
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  Menée sur les génomes tumoraux et non tumoraux de 4 patients atteints d'un carcinome hépatocellulaire, cette étude de séquençage dresse la cartographie des anomalies de l'ADN des cellules tumorales induites par l'intégration du génome du virus de l'hépatite B

  “The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients”

  • Jiang, Zhaoshi;Jhunjhunwala, Suchit;Liu, Jinfeng;Haverty, Peter M.;Kennemer, Michael I.;Guan, Yinghui;Lee, William;Carnevali, Paolo;Stinson, Jeremy;Johnson, Stephanie;Diao, Jingyu;Yeung, Stacy;Jubb, Adrian;Ye, Weilan;Wu, Thomas D.;Kapadia, Sharookh B.;de Sauvage, Frederic J.;Gentleman, Robert C.;Stern, Howard M.;Seshagiri, Somasekar;Pant, Krishna P.;Modrusan, Zora;Ballinger, Dennis G;Zhang, Zemin

  Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC). HBV integration into the host genome has been reported but its scale, impact and contribution to HCC development is not clear. Here, we sequenced the tumor and non-tumor genomes (>80X coverage) and transcriptomes of four HCC patients and identified 255 HBV integration sites. Increased sequencing to 240X coverage revealed a proportionally higher number of integration sites. Clonal expansion of HBV-integrated hepatocytes was found specifically in tumor samples. We observe a diverse collection of genomic perturbations near viral integration sites, including direct gene disruption, viral promoter-driven human transcription, viral-human transcript fusion and DNA copy number alteration. Thus, we report the most comprehensive characterization of HBV integration in hepatocellular carcinoma patients. Such widespread random viral integration will likely increase carcinogenic opportunities in ...

  
  

Mots clés : Foie; Biologie (Aberrations chromosomiques)

Cette étude identifie un mécanisme de tumorigenèse par lequel, au cours de la mitose, des erreurs dans la ségrégation des chromosomes induisent des cassures de l'ADN

• DNA breaks and chromosome pulverization from errors in mitosis
  • Nature, sous presse, 2012 (résumé)
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  Cette étude identifie un mécanisme de tumorigenèse par lequel, au cours de la mitose, des erreurs dans la ségrégation des chromosomes induisent des cassures de l'ADN

  “DNA breaks and chromosome pulverization from errors in mitosis”

  • Crasta, Karen;Ganem, Neil J.;Dagher, Regina;Lantermann, Alexandra B.;Ivanova, Elena V.;Pan, Yunfeng;Nezi, Luigi;Protopopov, Alexei;Chowdhury, Dipanjan;Pellman, David

  The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for ‘chromothripsis’ ...

  
  

Mots clés : Cancer (général); Biologie (Aberrations chromosomiques)

Menée sur un modèle tri-dimensionnel de culture cellulaire, cette étude identifie un mécanisme par lequel une forme mutée du gène p53, en activant la voie de signalisation mévalonate, perturbe l'architecture des tissus mammaires

• Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway
  • Cell, Vol. 148 (1), pp. 244-258, 2012 (résumé)
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  Menée sur un modèle tri-dimensionnel de culture cellulaire, cette étude identifie un mécanisme par lequel une forme mutée du gène p53, en activant la voie de signalisation mévalonate, perturbe l'architecture des tissus mammaires

  “Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway”

  • Freed-Pastor, William A;Mizuno, Hideaki;Zhao, Xi;Langerød, Anita;Moon, Sung-Hwan;Rodriguez-Barrueco, Ruth;Barsotti, Anthony;Chicas, Agustin;Li, Wencheng;Polotskaia, Alla;Bissell, Mina J;Osborne, Timothy F;Tian, Bin;Lowe, Scott W;Silva, Jose M;Børresen-Dale, Anne-Lise;Levine, Arnold J;Bargonetti, Jill;Prives, Carol

  p53 is a frequent target for mutation in human tumors, and mutant p53 proteins can actively contribute to tumorigenesis. We employed a three-dimensional culture model in which nonmalignant breast epithelial cells form spheroids reminiscent of acinar structures found in vivo, whereas breast cancer cells display highly disorganized morphology. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the mevalonate pathway as significantly upregulated by mutant p53. Statins and sterol biosynthesis intermediates reveal that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with sterol gene promoters at least partly via SREBP transcription factors. Finally, p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors. These findings implicate the ...

  
  

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

Cet article passe en revue les travaux récents sur la régulation épigénétique de l'expression de divers gènes jouant un rôle de suppresseurs de tumeurs dans les carcinomes à cellules rénales

• Epigenetic regulation in RCC: opportunities for therapeutic intervention?
  • Nature Reviews Urology, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur la régulation épigénétique de l'expression de divers gènes jouant un rôle de suppresseurs de tumeurs dans les carcinomes à cellules rénales

  “Epigenetic regulation in RCC: opportunities for therapeutic intervention?”

  • Larkin, James;Goh, Xin Yi;Vetter, Marcus;Pickering, Lisa;Swanton, Charles

  Renal cell carcinoma (RCC) is a constellation of malignancies of different histological subtypes arising from the renal parenchyma. The clear cell histological subtype (ccRCC) accounts for around 75% of RCCs and is characterized by distinct genetic abnormalities, of which the loss of function of the von Hippel–Lindau (VHL) tumor suppressor gene is the most common. Inactivation of other tumor suppressor genes such as SETD2, KDM6A, KDM5C and PBRM1 has been reported in ccRCC—notably, the proteins encoded by these genes are involved in histone and chromatin regulation. Furthermore, the PBRM1 and SETD2 genes are located on the short arm of chromosome 3 near the VHL locus. Chromatin and histones modify gene expression and, as a consequence, their function is tightly regulated. Data from RNA interference (RNAi) assays suggest that loss of function of PBRM1 drives proliferation and growth of ccRCC, but the clinical relevance of this is unclear and restoring the function of these genes for ...

  
  

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

Menée sur des souris génétiquement modifiées, cette étude identifie le rôle joué par un mécanisme inflammatoire dans la formation d'une tumeur hépatique induite par la signalisation beta-caténine

• Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice
  • The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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  Menée sur des souris génétiquement modifiées, cette étude identifie le rôle joué par un mécanisme inflammatoire dans la formation d'une tumeur hépatique induite par la signalisation beta-caténine

  “Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice”

  • Anson, Marie;Crain-Denoyelle, Anne-Marie;Baud, Véronique;Chereau, Fanny;Gougelet, Angélique;Terris, Benoit;Yamagoe, Satoshi;Colnot, Sabine;Viguier, Mireille;Perret, Christine;Couty, Jean-Pierre

  Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding β-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of β-catenin–induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic β-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by β-catenin and activation of the NF-κB pathway. This led to a specific inflammatory response, the intensity of which determined the degree of tumor aggressiveness. The chemokine-like chemotactic factor leukocyte cell–derived chemotaxin 2 (LECT2) and invariant NKT (iNKT) cells were identified as key interconnected effectors of liver β-catenin–induced ...

  
  

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

Menée sur des tumeurs et des lignées cellulaires de cancer colorectal, ainsi qu'à l'aide de xénogreffes, cette étude montre que la myosine MYO1A exerce une fonction de suppresseur de tumeurs

• Brush border Myosin Ia has tumor suppressor activity in the intestine
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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  Menée sur des tumeurs et des lignées cellulaires de cancer colorectal, ainsi qu'à l'aide de xénogreffes, cette étude montre que la myosine MYO1A exerce une fonction de suppresseur de tumeurs

  “Brush border Myosin Ia has tumor suppressor activity in the intestine”

  • Mazzolini, Rocco;Dopeso, Higinio;Mateo-Lozano, Silvia;Chang, Wakam;Rodrigues, Paulo;Bazzocco, Sarah;Alazzouzi, Hafid;Landolfi, Stefania;Hernández-Losa, Javier;Andretta, Elena;Alhopuro, Pia;Espín, Eloy;Armengol, Manel;Tabernero, Josep;Ramón y Cajal, Santiago;Kloor, Matthias;Gebert, Johannes;Mariadason, John M.;Schwartz, Simo;Aaltonen, Lauri A.;Mooseker, Mark S.;Arango, Diego

  The loss of the epithelial architecture and cell polarity/differentiation is known to be important during the tumorigenic process. Here we demonstrate that the brush border protein Myosin Ia (MYO1A) is important for polarization and differentiation of colon cancer cells and is frequently inactivated in colorectal tumors by genetic and epigenetic mechanisms. MYO1A frame-shift mutations were observed in 32% (37 of 116) of the colorectal tumors with microsatellite instability analyzed, and evidence of promoter methylation was observed in a significant proportion of colon cancer cell lines and primary colorectal tumors. The loss of polarization/differentiation resulting from MYO1A inactivation is associated with higher tumor growth in soft agar and in a xenograft model. In addition, the progression of genetically and carcinogen-initiated intestinal tumors was significantly accelerated in Myo1a knockout mice compared with Myo1a wild-type animals. Moreover, MYO1A tumor expression was found ...

  
  

Mots clés : Colon-rectum; Biologie (Oncogènes et suppresseurs de tumeurs)

Cet article passe en revue les travaux récents sur le rôle de petits ARNs nucléolaires non codants dans l'oncogenèse

• Are snoRNAs and snoRNA host genes new players in cancer?
  • Nature Reviews Cancer, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur le rôle de petits ARNs nucléolaires non codants dans l'oncogenèse

  “Are snoRNAs and snoRNA host genes new players in cancer?”

  • Williams, Gwyn T.;Farzaneh, Farzin

  Small nucleolar RNAs (snoRNAs) have long been considered important but unglamorous elements in the production of the protein synthesis machinery of the cell. Recently, however, several independent lines of evidence have indicated that these non-coding RNAs might have crucial roles in controlling cell behaviour, and snoRNA dysfunction could consequently contribute to oncogenesis in previously unsuspected ways.

  
  

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

Menée in vitro, cette étude met en évidence un mécanisme de régulation, par le gène Mdm2, de l'activation du gène p53 en réponse à une atteinte à l'ADN

• The p53 mRNA-Mdm2 Interaction Controls Mdm2 Nuclear Trafficking and Is Required for p53 Activation following DNA Damage
  • Cancer cell, Vol. 21 (1), pp. 25-35, 2012 (article en libre accès)
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  Menée in vitro, cette étude met en évidence un mécanisme de régulation, par le gène Mdm2, de l'activation du gène p53 en réponse à une atteinte à l'ADN

  “The p53 mRNA-Mdm2 Interaction Controls Mdm2 Nuclear Trafficking and Is Required for p53 Activation following DNA Damage”

  • Gajjar, Madhavsai;Candeias, Marco M;Malbert-Colas, Laurence;Mazars, Anne;Fujita, Jun;Olivares-Illana, Vanesa;Fåhraeus, Robin

  The ATM kinase and p53 are key tumor suppressor factors that control the genotoxic stress response pathway. The ATM substrate Mdm2 controls p53 activity by either targeting p53 for degradation or promoting its synthesis by binding the p53 mRNA. The physiological role and regulation of Mdm2's dual function toward p53 is not known. Here we show that ATM-dependent phosphorylation of Mdm2 at Ser395 is required for the p53 mRNA-Mdm2 interaction. This event also promotes SUMO-conjugation of Mdm2 and its nucleoli accumulation. Interfering with the p53 mRNA-Mdm2 interaction prevents p53 stabilization and activation following DNA damage. These results demonstrate how ATM activity switches Mdm2 from a negative to a positive regulator of p53 via the p53 mRNA. º p53 stabilization following genotoxic stress requires the p53 mRNA-Mdm2 interaction º Mdm2 acts as a positive regulator of p53 activity following DNA damage º ATM promotes p53 mRNA-Mdm2 interaction via phosphorylation on Mdm2 S395 º ...

  
  
• Mdm2's Dilemma: To Degrade or To Translate p53?
  • Cancer cell, Vol. 21 (1), pp. 3-5, 2012 (commentaire)
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  Menée in vitro, cette étude met en évidence un mécanisme de régulation, par le gène Mdm2, de l'activation du gène p53, en réponse à une atteinte à l'ADN

  “Mdm2's Dilemma: To Degrade or To Translate p53?”

  • Hamard, Pierre-Jacques ; Manfredi, James J

  In this issue of Cancer Cell, Gajjar et al. provide insight into how Mdm2 can both inhibit and enhance p53 activity. In the basal setting, Mdm2 binds p53 and promotes p53 degradation. Under stress conditions, ATM-dependent phosphorylation of Mdm2 results in its recruitment to p53 mRNA, thereby stimulating p53 translation.

  
  

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

Cette étude décrit un modèle murin transgénique permettant d'étudier in vivo le fonctionnement de la voie de signalisation p53

• Using targeted transgenic reporter mice to study promoter-specific p53 transcriptional activity
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Cette étude décrit un modèle murin transgénique permettant d'étudier in vivo le fonctionnement de la voie de signalisation p53

  “Using targeted transgenic reporter mice to study promoter-specific p53 transcriptional activity”

  • Goh, Amanda M.;Lim, Chin Yan;Chiam, Poh Cheang;Li, Ling;Mann, Michael B.;Mann, Karen M.;Menendez, Sergio;Lane, David P.

  The p53 transcription factor modulates gene expression programs that induce cell cycle arrest, senescence, or apoptosis, thereby preventing tumorigenesis. However, the mechanisms by which these fates are selected are unclear. Our objective is to understand p53 target gene selection and, thus, enable its optimal manipulation for cancer therapy. We have generated targeted transgenic reporter mice in which EGFP expression is driven by p53 transcriptional activity at a response element from either the p21 or Puma promoter, which induces cell cycle arrest/senescence and apoptosis, respectively. We demonstrate that we could monitor p53 activity in vitro and in vivo and detect variations in p53 activity depending on the response element, tissue type, and stimulus, thereby validating our reporter system and illustrating its utility for preclinical drug studies. Our results also show that the sequence of the p53 response element itself is sufficient to strongly influence p53 target gene ...

  
  

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

Menée in vitro et in vivo, cette étude identifie un mécanisme par lequel p53 inhibe l'angiogenèse en induisant la production d'un facteur antiangiogénique dérivé d'un collagène (arresten)

• p53 inhibits angiogenesis by inducing the production of Arresten
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude identifie un mécanisme par lequel p53 inhibe l'angiogenèse en induisant la production d'un facteur antiangiogénique dérivé d'un collagène (arresten)

  “p53 inhibits angiogenesis by inducing the production of Arresten”

  • Assadian, Sarah;El-Assaad, Wisal;Wang, Xue Q.D.;Gannon, Philippe O.;Barres, Veronique;Latour, Mathieu;Mes-Masson, Anne-Marie;Saad, Fred;Sado, Yoshikazu;Dostie, Josée;Teodoro, Jose

  Several types of collagen contain cryptic antiangiogenic non-collagenous domains that are released upon proteolysis of extracellular matrix (ECM). Among those is Arresten, a collagen-derived antiangiogenic factor (CDAF) that is processed from alpha 1 collagen 4. However, the conditions under which Arresten is released from collagen 4 in vivo or whether the protein functions in tumor suppressor pathways remain unknown. Here we show that p53 induces the expression of 1 collagen 4 and release of Arresten containing fragments from the ECM. Comparison of the transcriptional activation of COL4A1 with other CDAF containing genes revealed that COL4A1 is a major antiangiogenic gene induced by p53 in human adenocarinoma cells. p53 directly activated transcription of the COL4A1 gene by binding to an enhancer region 26kbp downstream of its 3 prime end. p53 also stabilized the expression of full length 1 collagen 4 by upregulation of alpha (II) prolyl-hydroxylase and increased the release of ...

  
  

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

Menée sur un modèle murin de gliome, cette étude montre que la capacité d'auto-renouvellement des cellules tumorales n'est pas nécessairement associée à leur capacité de prolifération

• Self-Renewal Does Not Predict Tumor Growth Potential in Mouse Models of High-Grade Glioma
  • Cancer cell, Vol. 21 (1), pp. 11-24, 2012 (résumé)
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  Menée sur un modèle murin de gliome, cette étude montre que la capacité d'auto-renouvellement des cellules tumorales n'est pas nécessairement associée à leur capacité de prolifération

  “Self-Renewal Does Not Predict Tumor Growth Potential in Mouse Models of High-Grade Glioma”

  • Barrett, Lindy E;Granot, Zvi;Coker, Courtney;Iavarone, Antonio;Hambardzumyan, Dolores;Holland, Eric C;Nam, Hyung-song;Benezra, Robert

  Within high-grade gliomas, the precise identities and functional roles of stem-like cells remain unclear. In the normal neurogenic niche, ID (Inhibitor of DNA-binding) genes maintain self-renewal and multipotency of adult neural stem cells. Using PDGF- and KRAS-driven murine models of gliomagenesis, we show that high Id1 expression (Id1high) identifies tumor cells with high self-renewal capacity, while low Id1 expression (Id1low) identifies tumor cells with proliferative potential but limited self-renewal capacity. Surprisingly, Id1low cells generate tumors more rapidly and with higher penetrance than Id1high cells. Further, eliminating tumor cell self-renewal through deletion of Id1 has modest effects on animal survival, while knockdown of Olig2 within Id1low cells has a significant survival benefit, underscoring the importance of non-self-renewing lineages in disease progression. º Id1 identifies self-renewing glioma cells º Self-renewal is not required for glioma growth in PDGF- ...

  
  
• Spheres without Influence: Dissociating In Vitro Self-Renewal from Tumorigenic Potential in Glioma
  • Cancer cell, Vol. 21 (1), pp. 1-3, 2012 (commentaire)
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  Menée sur un modèle murin de gliome, cette étude montre que la capacité d'auto-renouvellement des cellules tumorales n'est pas nécessairement associée à leur capacité de prolifération

  “Spheres without Influence: Dissociating In Vitro Self-Renewal from Tumorigenic Potential in Glioma”

  • Read, Tracy-Ann ; Wechsler-Reya, Robert J

  The capacity for self-renewal is thought to be a critical property of tumor-initiating cells. This capacity is often associated with the ability to generate spheres in vitro. In this issue of Cancer Cell, Barrett et al. show that cells lacking sphere-forming ability can still be very efficient at propagating tumors.

  
  

Mots clés : Système nerveux central; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur les liens entre cellules souches cancéreuses, transition épithélio-mésenchymateuse et résistance thérapeutique dans le cancer du sein

• Epithelial-mesenchymal transition, cancer stem cells and treatment resistance
  • Breast Cancer Research, Vol. 14 (1), pp. 202, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur les liens entre cellules souches cancéreuses, transition épithélio-mésenchymateuse et résistance thérapeutique dans le cancer du sein

  “Epithelial-mesenchymal transition, cancer stem cells and treatment resistance”

  • Dave, Bhuvanesh;Mittal, Vivek;Tan, Nicholas;Chang, Jenny

  Mortality from breast cancer has steadily been declining over the last decade, primarily due to earlier detection, adjuvant therapies and the advent of targeted therapies for ER positive and HER2 positive cancers [1, 2]. Despite these advances, a large number of patients relapse after an initial response to standard of care therapy. Novel therapies that prevent breast cancer relapse and metastasis are needed. An emerging hypothesis is that tumors contain a subpopulation of cells, called cancer stem cells (CSCs), which have the ability to self renew and regenerate the tumor. Increasingly, clinical evidence points to an intrinsic resistance to endocrine therapy and chemotherapy of this subpopulation of cancer stem cells [3]. The residual tumors after chemotherapy are enriched for CSCs and have a gene signature with hallmarks of epithelial-mesenchymal transition (EMT) like properties [3, 4]. This review is a step in developing an understanding of the nature of treatment resistance and ...

  
  

Mots clés : Sein; Biologie (Progression et métastases)

Menée sur un modèle murin de cancer de la prostate résistant à la castration, cette étude met en évidence l'activation spécifique des voies de signalisation de certaines tyrosine kinases

• Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Menée sur un modèle murin de cancer de la prostate résistant à la castration, cette étude met en évidence l'activation spécifique des voies de signalisation de certaines tyrosine kinases

  “Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression”

  • Drake, Justin M.;Graham, Nicholas A.;Stoyanova, Tanya;Sedghi, Amir;Goldstein, Andrew S.;Cai, Houjian;Smith, Daniel A.;Zhang, Hong;Komisopoulou, Evangelia;Huang, Jiaoti;Graeber, Thomas G.;Witte, Owen N.

  Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbed non-tyrosine kinase oncogenes and pathways and detected a significant up-regulation of tyrosine phosphorylation at the carcinoma stage. Phosphotyrosine peptide enrichment and quantitative mass spectrometry identified oncogene-specific tyrosine kinase signatures, including activation of EGFR, ephrin type-A receptor 2 (EPHA2), and JAK2. Kinase:substrate relationship analysis of the phosphopeptides also revealed ABL1 and SRC tyrosine kinase activation. The observation of elevated tyrosine kinase ...

  
  

Mots clés : Prostate; Biologie (Progression et métastases)

Menée sur un modèle murin pour l'une et sur un modèle numérique pour l'autre, ces deux études suggèrent que, dans le cancer du pancréas, le processus métastatique débute de façon beaucoup plus précoce qu'on ne le pensait jusqu'à présent

• EMT and Dissemination Precede Pancreatic Tumor Formation
  • Cell, Vol. 148 (1), pp. 349-361, 2012 (résumé)
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  Menée sur un modèle murin pour l'une et sur un modèle numérique pour l'autre, ces deux études suggèrent que, dans le cancer du pancréas, le processus métastatique débute de façon beaucoup plus précoce qu'on ne le pensait jusqu'à présent

  “EMT and Dissemination Precede Pancreatic Tumor Formation”

  • Rhim, Andrew D;Mirek, Emily T;Aiello, Nicole M;Maitra, Anirban;Bailey, Jennifer M;McAllister, Florencia;Reichert, Maximilian;Beatty, Gregory L;Rustgi, Anil K;Vonderheide, Robert H;Leach, Steven D;Stanger, Ben Z

  Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation ...

  
  
• Computational Modeling of Pancreatic Cancer Reveals Kinetics of Metastasis Suggesting Optimum Treatment Strategies
  • Cell, Vol. 148 (1), pp. 362-375, 2012 (résumé)
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  Menée sur un modèle murin pour l'une et sur un modèle numérique pour l'autre, ces deux études suggèrent que, dans le cancer du pancréas, le processus métastatique débute de façon beaucoup plus précoce qu'on ne le pensait jusqu'à présent

  “Computational Modeling of Pancreatic Cancer Reveals Kinetics of Metastasis Suggesting Optimum Treatment Strategies”

  • Haeno, Hiroshi ; Gonen, Mithat ; Davis, Meghan B ; Herman, Joseph M ; Iacobuzio-Donahue, Christine A ; Michor, Franziska

  Pancreatic cancer is a leading cause of cancer-related death, largely due to metastatic dissemination. We investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with comprehensive data of 228 patients, 101 of whom had autopsies. We found that pancreatic cancer growth is initially exponential. After estimating the rates of pancreatic cancer growth and dissemination, we determined that patients likely harbor metastases at diagnosis and predicted the number and size distribution of metastases as well as patient survival. These findings were validated in an independent database. Finally, we analyzed the effects of different treatment modalities, finding that therapies that efficiently reduce the growth rate of cells earlier in the course of treatment appear to be superior to upfront tumor resection. These predictions can be validated in the clinic. Our interdisciplinary approach provides insights into the dynamics of pancreatic ...

  
  
• Understanding Metastasis in Pancreatic Cancer: A Call for New Clinical Approaches
  • Cell, Vol. 148 (1), pp. 21-23, 2012 (commentaire)
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  Menée sur un modèle murin pour l'une et sur un modèle numérique pour l'autre, ces deux études suggèrent que, dans le cancer du pancréas, le processus métastatique débute de façon beaucoup plus précoce qu'on ne le pensait jusqu'à présent

  “Understanding Metastasis in Pancreatic Cancer: A Call for New Clinical Approaches”

  • Tuveson, David A ; Neoptolemos, John P

  Although metastasis is a major cause of morbidity and mortality in patients with pancreatic cancer, the requisite events are currently unknown. In this issue of Cell, Haeno et al. and Rhim et al. propose that metastasis occurs much earlier than previously anticipated, with clear implications for improving patient care.

  
  

Mots clés : Pancréas; Biologie (Progression et métastases)

Menée sur des modèles murins, cette étude met en évidence la coopération, à l'intérieur du micro-environnement tumoral, entre cellules cancéreuses et cellules non malignes du stroma pour produire une enzyme, APN, et favoriser l'angiogenèse, la croissance tumorale et le processus métastatique

• Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Menée sur des modèles murins, cette étude met en évidence la coopération, à l'intérieur du micro-environnement tumoral, entre cellules cancéreuses et cellules non malignes du stroma pour produire une enzyme, APN, et favoriser l'angiogenèse, la croissance tumorale et le processus métastatique

  “Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment”

  • Guzman-Rojas, Liliana;Rangel, Roberto;Salameh, Ahmad;Edwards, Julianna K.;Dondossola, Eleonora;Kim, Yun-Gon;Saghatelian, Alan;Giordano, Ricardo J.;Kolonin, Mikhail G.;Staquicini, Fernanda I.;Koivunen, Erkki;Sidman, Richard L.;Arap, Wadih;Pasqualini, Renata

  Processes that promote cancer progression such as angiogenesis require a functional interplay between malignant and nonmalignant cells in the tumor microenvironment. The metalloprotease aminopeptidase N (APN; CD13) is often overexpressed in tumor cells and has been implicated in angiogenesis and cancer progression. Our previous studies of APN-null mice revealed impaired neoangiogenesis in model systems without cancer cells and suggested the hypothesis that APN expressed by nonmalignant cells might promote tumor growth. We tested this hypothesis by comparing the effects of APN deficiency in allografted malignant (tumor) and nonmalignant (host) cells on tumor growth and metastasis in APN-null mice. In two independent tumor graft models, APN activity in both the tumors and the host cells cooperate to promote tumor vascularization and growth. Loss of APN expression by the host and/or the malignant cells also impaired lung metastasis in experimental mouse models. Thus, cooperation in APN ...

  
  

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

Cet article analyse la pertinence des modèles murins actuels pour l'étude des bases moléculaires du cancer à l'ère des traitements personnalisés

• Mouse models of cancer: does the strain matter?
  • Nature Reviews Cancer, sous presse, 2012 (résumé)
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  Cet article analyse la pertinence des modèles murins actuels pour l'étude des bases moléculaires du cancer à l'ère des traitements personnalisés

  “Mouse models of cancer: does the strain matter?”

  • Hunter, Kent W.

  Mouse models are indispensible tools for understanding the molecular basis of cancer. However, despite the invaluable data provided regarding tumour biology, owing to inbreeding, current mouse models fail to accurately model human populations. Polymorphism is the essential characteristic that makes each of us unique humans, with different disease susceptibility, presentation and progression. Therefore, as we move closer towards designing clinical treatment that is based on an individual's unique biological makeup, it is imperative that we understand how inherited variability influences cancer phenotypes, how it can confound experiments and how it can be exploited to reveal new truths about cancer biology.

  
  

Mots clés : Cancer (général); Biologie (Ressources et infrastructures (Biologie))