Biologie

Menée sur 92 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un médulloblastome primitif, cette étude de séquençage des exons identifie des mutations somatiques en association avec des sous-types spécifiques de la maladie

• Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations
  • Nature, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur 92 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un médulloblastome primitif, cette étude de séquençage des exons identifie des mutations somatiques en association avec des sous-types spécifiques de la maladie

  “Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations”

  • Pugh, Trevor J.;Weeraratne, Shyamal Dilhan;Archer, Tenley C.;Pomeranz Krummel, Daniel A.;Auclair, Daniel;Bochicchio, James;Carneiro, Mauricio O.;Carter, Scott L.;Cibulskis, Kristian;Erlich, Rachel L.;Greulich, Heidi;Lawrence, Michael S.;Lennon, Niall J.;McKenna, Aaron;Meldrim, James;Ramos, Alex H.;Ross, Michael G.;Russ, Carsten;Shefler, Erica;Sivachenko, Andrey;Sogoloff, Brian;Stojanov, Petar;Tamayo, Pablo;Mesirov, Jill P.;Amani, Vladimir;Teider, Natalia;Sengupta, Soma;Francois, Jessica Pierre;Northcott, Paul A.;Taylor, Michael D.;Yu, Furong;Crabtree, Gerald R.;Kautzman, Amanda G.;Gabriel, Stacey B.;Getz, Gad;Jager, Natalie;Jones, David T. W.;Lichter, Peter;Pfister, Stefan M.;Roberts, Thomas M.;Meyerson, Matthew;Pomeroy, Scott L.;Cho, Yoon-Jae

  Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 ...

  
  

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

Menée sur 121 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un mélanome, cette étude identifie des mutations conductrices associées à une exposition aux rayonnements ultraviolets

• A Landscape of Driver Mutations in Melanoma
  • Cell, Vol. 150 (2), pp. 251-263, 2012 (résumé)
  Détails

  Fermer

  Menée sur 121 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un mélanome, cette étude identifie des mutations conductrices associées à une exposition aux rayonnements ultraviolets

  “A Landscape of Driver Mutations in Melanoma”

  • Hodis, Eran;Watson, Ian R;Kryukov, Gregory V;Arold, Stefan T;Imielinski, Marcin;Theurillat, Jean-Philippe;Nickerson, Elizabeth;Auclair, Daniel;Li, Liren;Place, Chelsea;DiCara, Daniel;Ramos, Alex H;Lawrence, Michael S;Cibulskis, Kristian;Sivachenko, Andrey;Voet, Douglas;Saksena, Gordon;Stransky, Nicolas;Onofrio, Robert C;Winckler, Wendy;Ardlie, Kristin;Wagle, Nikhil;Wargo, Jennifer;Chong, Kelly;Morton, Donald L;Stemke-Hale, Katherine;Chen, Guo;Noble, Michael;Meyerson, Matthew;Ladbury, John E;Davies, Michael A;Gershenwald, Jeffrey E;Wagner, Stephan N;Hoon, Dave S B.;Schadendorf, Dirk;Lander, Eric S;Gabriel, Stacey B;Getz, Gad;Garraway, Levi A;Chin, Lynda

  Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which RAC1, PPP6C, and STK19 harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence ...

  
  

Mots clés : Mélanome; Biologie (Aberrations chromosomiques)

Menée sur 24 échantillons prélevés sur des patients atteints d'une leucémie myéloïde aiguë et sur des cellules souches hématopoïétiques prélevées sur 7 témoins sains d'âges différents, cette étude suggère que la plupart des mutations identifiées dans les génomes de leucémie relèvent d'événements aléatoires ayant eu lieu dans les cellules souches préalablement à la mutation initiatrice de la maladie

• The Origin and Evolution of Mutations in Acute Myeloid Leukemia
  • Cell, Vol. 150 (2), pp. 264-278, 2012 (résumé)
  Détails

  Fermer

  Menée sur 24 échantillons prélevés sur des patients atteints d'une leucémie myéloïde aiguë et sur des cellules souches hématopoïétiques prélevées sur 7 témoins sains d'âges différents, cette étude suggère que la plupart des mutations identifiées dans les génomes de leucémie relèvent d'événements aléatoires ayant eu lieu dans les cellules souches préalablement à la mutation initiatrice de la maladie

  “The Origin and Evolution of Mutations in Acute Myeloid Leukemia”

  • Welch, John S;Ley, Timothy J;Link, Daniel C;Miller, Christopher A;Larson, David E;Koboldt, Daniel C;Wartman, Lukas D;Lamprecht, Tamara L;Liu, Fulu;Xia, Jun;Kandoth, Cyriac;Fulton, Robert S;McLellan, Michael D;Dooling, David J;Wallis, John W;Chen, Ken;Harris, Christopher C;Schmidt, Heather K;Kalicki-Veizer, Joelle M;Lu, Charles;Zhang, Qunyuan;Lin, Ling;O Laughlin, Michelle D;McMichael, Joshua F;Delehaunty, Kim D;Fulton, Lucinda A;Magrini, Vincent J;McGrath, Sean D;Demeter, Ryan T;Vickery, Tammi L;Hundal, Jasreet;Cook, Lisa L;Swift, Gary W;Reed, Jerry P;Alldredge, Patricia A;Wylie, Todd N;Walker, Jason R;Watson, Mark A;Heath, Sharon E;Shannon, William D;Varghese, Nobish;Nagarajan, Rakesh;Payton, Jacqueline E;Baty, Jack D;Kulkarni, Shashikant;Klco, Jeffery M;Tomasson, Michael H;Westervelt, Peter;Walter, Matthew J;Graubert, Timothy A;DiPersio, John F;Ding, Li;Mardis, Elaine R;Wilson, Richard K

  Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is captured as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can ...

  
  

Mots clés : Leucémie; Biologie (Aberrations chromosomiques)

Menée sur 276 échantillons tumoraux prélevés sur des patients atteints d'un carcinome colorectal, cette étude identifie des mutations, des anomalies du nombre de copies de gènes et des translocations chromosomiques associées aux carcinomes du côlon et du rectum

• Comprehensive molecular characterization of human colon and rectal cancer
  • Nature, Vol. 487 (7407), pp. 330-337, 2012 (article en libre accès)
  Détails

  Fermer

  Menée sur 276 échantillons tumoraux prélevés sur des patients atteints d'un carcinome colorectal, cette étude identifie des mutations, des anomalies du nombre de copies de gènes et des translocations chromosomiques associées aux carcinomes du côlon et du rectum

  “Comprehensive molecular characterization of human colon and rectal cancer”

  •

  To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and ...

  
  

Mots clés : Colon-rectum; Biologie (Aberrations chromosomiques)

Cette étude met en évidence le rôle important joué par l'organisation de la chromatine pour rendre compte de la variation du taux de mutations somatiques entre diverses régions du génome

• Chromatin organization is a major influence on regional mutation rates in human cancer cells
  • Nature, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cette étude met en évidence le rôle important joué par l'organisation de la chromatine pour rendre compte de la variation du taux de mutations somatiques entre diverses régions du génome

  “Chromatin organization is a major influence on regional mutation rates in human cancer cells”

  • Schuster-Bockler, Benjamin;Lehner, Ben

  Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.

  
  

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

Cette étude présente une méthode d’interprétation des génomes de cancer à partir de l’analyse systématique de perturbations des réseaux cellulaires de l’hôte par des protéines virales tumorales

• Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins
  • Nature, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cette étude présente une méthode d’interprétation des génomes de cancer à partir de l’analyse systématique de perturbations des réseaux cellulaires de l’hôte par des protéines virales tumorales

  “Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins”

  • Rozenblatt-Rosen, Orit;Deo, Rahul C.;Padi, Megha;Adelmant, Guillaume;Calderwood, Michael A.;Rolland, Thomas;Grace, Miranda;Dricot, Amelie;Askenazi, Manor;Tavares, Maria;Pevzner, Samuel J.;Abderazzaq, Fieda;Byrdsong, Danielle;Carvunis, Anne-Ruxandra;Chen, Alyce A.;Cheng, Jingwei;Correll, Mick;Duarte, Melissa;Fan, Changyu;Feltkamp, Mariet C.;Ficarro, Scott B.;Franchi, Rachel;Garg, Brijesh K.;Gulbahce, Natali;Hao, Tong;Holthaus, Amy M.;James, Robert;Korkhin, Anna;Litovchick, Larisa;Mar, Jessica C.;Pak, Theodore R.;Rabello, Sabrina;Rubio, Renee;Shen, Yun;Singh, Saurav;Spangle, Jennifer M.;Tasan, Murat;Wanamaker, Shelly;Webber, James T.;Roecklein-Canfield, Jennifer;Johannsen, Eric;Barabasi, Albert-Laszlo;Beroukhim, Rameen;Kieff, Elliott;Cusick, Michael E.;Hill, David E.;Munger, Karl;Marto, Jarrod A.;Quackenbush, John;Roth, Frederick P.;DeCaprio, James A.;Vidal, Marc

  Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype–phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or ‘passenger’, cancer mutations from causal, or ‘driver’, mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The ...

  
  

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

Menée sur 35 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'une tumeur rhabdoïde, cette étude de séquençage des exons met en évidence un faible taux de mutations et montre que la perte du gène SMARCB1, impliqué dans le remodelage de la chromatine, est le seul événement génomique récurrent

• A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers
  • The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
  Détails

  Fermer

  Menée sur 35 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'une tumeur rhabdoïde, cette étude de séquençage des exons met en évidence un faible taux de mutations et montre que la perte du gène SMARCB1, impliqué dans le remodelage de la chromatine, est le seul événement génomique récurrent

  “A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers”

  • Lee, Ryan S.;Stewart, Chip;Carter, Scott L.;Ambrogio, Lauren;Cibulskis, Kristian;Sougnez, Carrie;Lawrence, Michael S.;Auclair, Daniel;Mora, Jaume;Golub, Todd R.;Biegel, Jaclyn A.;Getz, Gad;Roberts, Charles W. M.

  Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers and the emergence of mutations in genes that encode chromatin remodelers raise the possibility that perturbation of chromatin structure and epigenetic regulation are capable of driving cancer formation. Here we sequenced the exomes of 35 rhabdoid tumors, highly aggressive cancers of early childhood characterized by biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. We identified an extremely low rate of mutation, with loss of SMARCB1 being essentially the sole recurrent event. Indeed, in 2 of the cancers there were no other identified mutations. Our results demonstrate that high mutation rates are dispensable for the genesis of cancers driven by mutation of a chromatin remodeling complex. Consequently, cancer can be a remarkably genetically simple disease.

  
  

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

Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur des patients atteints d'un astrocytome de haut grade, cette étude met en évidence un mécanisme par lequel, dans le cerveau juvénile, des cellules précurseurs neuronales sont susceptibles d'induire la mort des cellules tumorales en stimulant l'expression du récepteur TRPV1

• Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1
  • Nature Medicine, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur des patients atteints d'un astrocytome de haut grade, cette étude met en évidence un mécanisme par lequel, dans le cerveau juvénile, des cellules précurseurs neuronales sont susceptibles d'induire la mort des cellules tumorales en stimulant l'expression du récepteur TRPV1

  “Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1”

  • Stock, Kristin;Kumar, Jitender;Synowitz, Michael;Petrosino, Stefania;Imperatore, Roberta;Smith, Ewan St J.;Wend, Peter;Purfurst, Bettina;Nuber, Ulrike A.;Gurok, Ulf;Matyash, Vitali;Walzlein, Joo-Hee;Chirasani, Sridhar R.;Dittmar, Gunnar;Cravatt, Benjamin F.;Momma, Stefan;Lewin, Gary R.;Ligresti, Alessia;Petrocellis, Luciano De;Cristino, Luigia;Marzo, Vincenzo Di;Kettenmann, Helmut;Glass, Rainer

  Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic ...

  
  

Mots clés : Système nerveux central; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel MDM4 induit un dysfonctionnement du suppresseur de tumeurs p53 dans les mélanomes cutanés

• MDM4 is a key therapeutic target in cutaneous melanoma
  • Nature Medicine, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel MDM4 induit un dysfonctionnement du suppresseur de tumeurs p53 dans les mélanomes cutanés

  “MDM4 is a key therapeutic target in cutaneous melanoma”

  • Gembarska, Agnieszka;Luciani, Flavie;Fedele, Clare;Russell, Elisabeth A.;Dewaele, Michael;Villar, Stephanie;Zwolinska, Aleksandra;Haupt, Sue;de Lange, Job;Yip, Dana;Goydos, James;Haigh, Jody J.;Haupt, Ygal;Larue, Lionel;Jochemsen, Aart;Shi, Hubing;Moriceau, Gatien;Lo, Roger S.;Ghanem, Ghanem;Shackleton, Mark;Bernal, Federico;Marine, Jean-Christophe

  The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma—a highly chemotherapy-resistant disease—TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (~65%) of stage I–IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key ...

  
  

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

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, via l'activation des signalisations NOTCH et AKT, des hépatocytes peuvent induire un cholangiocarcinome intrahépatique

• Cholangiocarcinomas can originate from hepatocytes in mice
  • The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
  Détails

  Fermer

  Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, via l'activation des signalisations NOTCH et AKT, des hépatocytes peuvent induire un cholangiocarcinome intrahépatique

  “Cholangiocarcinomas can originate from hepatocytes in mice”

  • Fan, Biao;Malato, Yann;Calvisi, Diego F.;Naqvi, Syed;Razumilava, Nataliya;Ribback, Silvia;Gores, Gregory J.;Dombrowski, Frank;Evert, Matthias;Chen, Xin;Willenbring, Holger

  Intrahepatic cholangiocarcinomas (ICCs) are primary liver tumors with a poor prognosis. The development of effective therapies has been hampered by a limited understanding of the biology of ICCs. Although ICCs exhibit heterogeneity in location, histology, and marker expression, they are currently thought to derive invariably from the cells lining the bile ducts, biliary epithelial cells (BECs), or liver progenitor cells (LPCs). Despite lack of experimental evidence establishing BECs or LPCs as the origin of ICCs, other liver cell types have not been considered. Here we show that ICCs can originate from fully differentiated hepatocytes. Using a mouse model of hepatocyte fate tracing, we found that activated NOTCH and AKT signaling cooperate to convert normal hepatocytes into biliary cells that act as precursors of rapidly progressing, lethal ICCs. Our findings suggest a previously overlooked mechanism of human ICC formation that may be targetable for anti-ICC therapy.

  
  

Mots clés : Voies biliaires; Biologie (Progression et métastases)

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un cancer primitif de la vessie, cette étude met en évidence le rôle joué par la voie de signalisation Hedgehog dans la progression de la maladie

• Hedgehog Signaling Regulates Bladder Cancer Growth And Tumorigenicity
  • Cancer Research, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un cancer primitif de la vessie, cette étude met en évidence le rôle joué par la voie de signalisation Hedgehog dans la progression de la maladie

  “Hedgehog Signaling Regulates Bladder Cancer Growth And Tumorigenicity”

  • Fei, Dennis Liang;Sanchez-Mejias, Avencia;Wang, Zhiqiang;Flaveny, Colin;Long, Jun;Singh, Samer;Rodriguez-Blanco, Jezabel;Tokhunts, Robert;Giambelli, Camilla;Briegel, Karoline J.;Schulz, Wolfgang A.;Gandolfi, A. Jay;Karagas, Margaret;Zimmers, Teresa A.;Jorda, Merce;Bejarano, Pablo;Capobianco, Anthony J.;Robbins, David J.

  The role of HEDGEHOG (HH) signaling in bladder cancer remains controversial. The gene encoding the HH receptor and negative regulator PATCHED1 (PTCH1) resides on a region of chromosome 9q, one copy of which is frequently lost in bladder cancer. Inconsistent with PTCH1 functioning as a classic tumor suppressor gene, loss-of-function mutations in the remaining copy of PTCH1 are not commonly found. Here, we provide direct evidence for a critical role of HH signaling in bladder carcinogenesis. We show that transformed human urothelial cells and many urothelial carcinoma (UC) cell lines exhibit constitutive HH signaling, which is required for their growth and tumorigenic properties. Surprisingly, rather than originating from loss of PTCH1, the constitutive HH activity observed in UC cell lines was HH ligand-dependent. Consistent with this finding, increased levels of HH and the HH target gene product GLI1 were found in resected human primary bladder tumors. Furthermore, based on the ...

  
  

Mots clés : Vessie; Biologie (Progression et métastases)

Menée in vitro, in vivo et sur des échantillons de carcinome invasif du sein, cette étude met en évidence le rôle joué par CCN6, une protéine de la matrice extracellulaire, dans la régulation des processus invasif et métastatique

• CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer
  • Cancer Research, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée in vitro, in vivo et sur des échantillons de carcinome invasif du sein, cette étude met en évidence le rôle joué par CCN6, une protéine de la matrice extracellulaire, dans la régulation des processus invasif et métastatique

  “CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer”

  • Pal, Anupama;Huang, Wei;Li, Xin;Toy, Kathy A.;Nicolovska-Coleska, Zaneta;Kleer, Celina G

  CCN6 is an extracellular matrix protein that exerts tumor suppressive functions in breast cancer, where its decreased expression is a feature of advanced disease. However, neither its role nor mechanism of action in breast cancer metastasis has been established. Bone morphogenetic proteins (BMPs), which constitute ligands of the TGF-β superfamily, are multifunctional cytokines that induce epithelial-mesenchymal transition (EMT), cell invasion and metastasis. In this study, we identify a CCN6-BMP4-TAK1 kinase signaling pathway that controls the ability of the p38 MAP kinase to regulate acinar morphogenesis and invasion of breast cells. ShRNA-mediated attenuation of CCN6 in human mammary epithelial (HME) cells led to BMP4 upregulation as a major response to exposure to the TGF-β superfamily. CCN6 attenuation also induced BMP4-mediated activation of the Smad-independent TAK1 and p38 kinases. Conversely, ectopic expression of CCN6 in breast cancer cells antagonized BMP4-mediated ...

  
  

Mots clés : Sein; Biologie (Progression et métastases)

Menée à l'aie d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation du système nerveux sympathique favorise la formation de métastases osseuses d'un cancer du sein

• Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
  • PLoS Biology, Vol. 10 (7), pp. e1001363, 2012 (article en libre accès)
  Détails

  Fermer

  Menée à l'aie d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation du système nerveux sympathique favorise la formation de métastases osseuses d'un cancer du sein

  “Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice”

  • Campbell, J. Preston;Karolak, Matthew R.;Ma, Yun;Perrien, Daniel S.;Masood-Campbell, S. Kathryn;Penner, Niki L.;Munoz, Steve A.;Zijlstra, Andries;Yang, Xiangli;Sterling, Julie A.;Elefteriou, Florent

  Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked ...

  
  

Mots clés : Sein; Biologie (Progression et métastases)

Menée à l'aide d'un modèle murin et de données portant sur 800 patientes atteintes d'un cancer du sein, cette étude identifie le rôle joué par lrf7, un facteur régulateur de l'interféron, dans la régulation des métastases osseuses

• Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape
  • Nature Medicine, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée à l'aide d'un modèle murin et de données portant sur 800 patientes atteintes d'un cancer du sein, cette étude identifie le rôle joué par lrf7, un facteur régulateur de l'interféron, dans la régulation des métastases osseuses

  “Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape”

  • Bidwell, Bradley N.;Slaney, Clare Y.;Withana, Nimali P.;Forster, Sam;Cao, Yuan;Loi, Sherene;Andrews, Daniel;Mikeska, Thomas;Mangan, Niamh E.;Samarajiwa, Shamith A.;Weerd, Nicole A. de;Gould, Jodee;Argani, Pedram;Moller, Andreas;Smyth, Mark J.;Anderson, Robin L.;Hertzog, Paul J.;Parker, Belinda S.

  Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8+ T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7-regulated genes in primary tumors was associated with prolonged bone metastasis–free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have ...

  
  

Mots clés : Sein; Biologie (Progression et métastases)

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en activant l'expression du facteur régulateur de la chromatine EZH2, le gène Kras et le récepteur des androgènes favorisent la progression d'un cancer de la prostate

• Collaboration of Kras and Androgen receptor signaling stimulates EZH2 expression and tumor propagating cells in prostate cancer
  • Cancer Research, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en activant l'expression du facteur régulateur de la chromatine EZH2, le gène Kras et le récepteur des androgènes favorisent la progression d'un cancer de la prostate

  “Collaboration of Kras and Androgen receptor signaling stimulates EZH2 expression and tumor propagating cells in prostate cancer”

  • cai, Houjian;Memarzadeh, Sanaz;Stoyanova, Tanya;Beharry, Zanna;Kraft, Andrew S;Witte, Owen

  Elevation of the chromatin repression factor EZH2 is associated with progression and poor prognosis in several human cancers, including prostate cancer. However, the mechanisms driving EZH2 expression are not fully understood. In this study, we investigated the functional synergy in prostate cancers in mice resulting from activation of the androgen receptor (AR), Kras and Akt, which drive three of the most frequently activated oncogenic signaling pathways in prostate cancer. While any two of these three events were sufficient to promote the formation and progression of prostate cancer, only the synergy of AR and Kras signaling could elevate EZH2 expression and expand prostate cancer progenitor cells in vivo. Our findings have revealed a genetic mechanism resulting in enhanced EZH2 expression during the progression of aggressive prostate cancer, with important implications for understanding how to target advanced disease where cancer progenitor cells may be critical.

  
  

Mots clés : Prostate; Biologie (Progression et métastases)

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par l'enzyme IDO dans le développement et le processus métastatique d'un cancer du poumon

• IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development
  • Cancer Discovery, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par l'enzyme IDO dans le développement et le processus métastatique d'un cancer du poumon

  “IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development”

  • Smith, Courtney;Chang, Mee Young;Parker, Katherine H.;Beury, Daniel W.;DuHadaway, James B.;Flick, Hollie E.;Boulden, Janette;Sutanto-Ward, Erika;Soler, Alejandro Peralta;Laury-Kleintop, Lisa D.;Mandik-Nayak, Laura;Metz, Richard;Ostrand-Rosenberg, Suzanne;Prendergast, George C.;Muller, Alexander J.

  Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma–derived pulmonary metastasis, we have found that IDO deficiency resulted in reduced lung tumor burden and improved survival in both models. Micro-computed tomographic (CT) imaging further revealed that the density of the underlying pulmonary blood vessels was significantly reduced in Ido1-nullizygous mice. During lung tumor and metastasis outgrowth, interleukin (IL)-6 induction was greatly attenuated in conjunction with the loss of IDO. Biologically, this resulted in a consequential impairment of ...

  
  

Mots clés : Poumon; Biologie (Progression et métastases)

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome pulmonaire, cette étude met en évidence le rôle joué par le récepteur EphA4 dans la régulation du processus invasif

• Global evaluation of Eph receptors and ephrins in lung adenocarcinomas identifies EphA4 as an inhibitor of cell migration and invasion
  • Molecular Cancer Therapeutics, sous presse, 2012 (résumé)
  Détails

  Fermer

  Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome pulmonaire, cette étude met en évidence le rôle joué par le récepteur EphA4 dans la régulation du processus invasif

  “Global evaluation of Eph receptors and ephrins in lung adenocarcinomas identifies EphA4 as an inhibitor of cell migration and invasion”

  • Saintigny, Pierre;Peng, Shaohua;Zhang, Li;Sen, Banibrata;Wistuba, Ignacio I.;Lippman, Scott M.;Girard, Luc;Minna, John D.;Heymach, John V.;Johnson, Faye M.

  The Eph family of receptors is the largest family of receptor tyrosine kinases, but it remains poorly studied in lung cancer. Our aim was to systematically explore the human Eph receptors and their ligands, the ephrins, in lung adenocarcinoma. The prognostic impact of Eph receptor and ephrin gene expression was analyzed using 2 independent cohorts of lung adenocarcinoma. Gene expression profiles in lung adenocarcinoma versus normal adjacent lung were studied in 3 independent cohorts and in cell lines. Gene expression profiles were validated with quantitative polymerase chain reaction (qPCR) and Western blotting in cell lines. Functional studies to assess the role of Eph receptor A4 (EphA4) were performed in vitro. The biological effects of EphA4 in lung cancer cell lines were assayed following overexpression and knockdown. Of the 11 Eph receptors and 8 ephrins analyzed, only EphA4 and ephrin A1 gene expression were consistently associated with an improved outcome in patients with lung ...

  
  

Mots clés : Poumon; Biologie (Progression et métastases)

Cet article passe en revue les limites des modèles expérimentaux et précliniques pour les recherches sur le cancer

• Issues to be considered when studying cancer in vitro
  • Critical Reviews in Oncology/Hematology, sous presse, 2012 (résumé)
  Détails

  Fermer

  Cet article passe en revue les limites des modèles expérimentaux et précliniques pour les recherches sur le cancer

  “Issues to be considered when studying cancer in vitro”

  • Čunderlíková, Beata

  Various cancer treatment approaches have shown promising results when tested preclinically. The results of clinical trials, however, are often disappointing. While searching for the reasons responsible for their failures, the relevance of experimental and preclinical models has to be taken into account. Possible factors that should be considered, including cell modifications during in vitro cultivation, lack of both the relevant interactions and the structural context in vitro have been summarized in the present review.

  
  

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