Biologie

Menée sur des souris transgéniques, cette étude met en évidence un mécanisme par lequel une mutation du gène ALK induit le développement d'un neuroblastome

• Targeted Expression of Mutated ALK Induces Neuroblastoma in Transgenic Mice
  • Science Translational Medicine, Vol. 4 (141), pp. 141ra91, 2012 (résumé)
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  Menée sur des souris transgéniques, cette étude met en évidence un mécanisme par lequel une mutation du gène ALK induit le développement d'un neuroblastome

  “Targeted Expression of Mutated ALK Induces Neuroblastoma in Transgenic Mice”

  • Heukamp, Lukas C.;Thor, Theresa;Schramm, Alexander;De Preter, Katleen;Kumps, Candy;De Wilde, Bram;Odersky, Andrea;Peifer, Martin;Lindner, Sven;Spruessel, Annika;Pattyn, Filip;Mestdagh, Pieter;Menten, Björn;Kuhfittig-Kulle, Steffi;Künkele, Annette;König, Katharina;Meder, Lydia;Chatterjee, Sampurna;Ullrich, Roland T.;Schulte, Stefanie;Vandesompele, Jo;Speleman, Frank;Büttner, Reinhard;Eggert, Angelika;Schulte, Johannes H.

  Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role of mutated ALK in tumorigenesis remains elusive. We demonstrate that targeted expression of the most frequent and aggressive variant, ALKF1174L, is tumorigenic in mice. Tumors resembled human neuroblastomas in morphology, metastasis pattern, gene expression, and the presence of neurosecretory vesicles as well as synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated the genetic spectrum of the disease. Chromosomal aberrations were syntenic to those in human neuroblastoma, including 17q gain and MYCN oncogene amplification. Targeted ALKF1174L and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted. Treatment of ALKF1174L transgenic mice with the ALK ...

  
  

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

Menée sur des lignées cellulaires de tumeurs humaines présentant des mutations du gène EGFR et sur une collection d'échantillons tumoraux prélevés sur des patients ayant développé une résistance à des inhibiteurs de l'activité tyrosine kinase d'EGFR, cette étude évalue la fréquence de mutations secondaires des gènes KRAS, NRAS, BRAF et MEK1

• Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Menée sur des lignées cellulaires de tumeurs humaines présentant des mutations du gène EGFR et sur une collection d'échantillons tumoraux prélevés sur des patients ayant développé une résistance à des inhibiteurs de l'activité tyrosine kinase d'EGFR, cette étude évalue la fréquence de mutations secondaires des gènes KRAS, NRAS, BRAF et MEK1

  “Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1”

  • Ohashi, Kadoaki;Sequist, Lecia V.;Arcila, Maria E.;Moran, Teresa;Chmielecki, Juliann;Lin, Ya-Lun;Pan, Yumei;Wang, Lu;de Stanchina, Elisa;Shien, Kazuhiko;Aoe, Keisuke;Toyooka, Shinichi;Kiura, Katsuyuki;Fernandez-Cuesta, Lynnette;Fidias, Panos;Yang, James Chih-Hsin;Miller, Vincent A.;Riely, Gregory J.;Kris, Mark G.;Engelman, Jeffrey A.;Vnencak-Jones, Cindy L.;Dias-Santagata, Dora;Ladanyi, Marc;Pao, William

  Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). ...

  
  

Mots clés : Poumon; Biologie (Aberrations chromosomiques)

Menée sur 1 478 échantillons tumoraux prélevés sur des patients américains atteints d'un adénocarcinome pulmonaire, cette étude évalue la prévalence de mutations activatrices de HER2 en association avec diverses caractéristiques clinico-pathologiques

• Prevalence, clinicopathologic associations and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Menée sur 1 478 échantillons tumoraux prélevés sur des patients américains atteints d'un adénocarcinome pulmonaire, cette étude évalue la prévalence de mutations activatrices de HER2 en association avec diverses caractéristiques clinico-pathologiques

  “Prevalence, clinicopathologic associations and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas”

  • Arcila, Maria E.;Chaft, Jamie E.;Nafa, Khedoudja;Roy-Chowdhuri, Sinchita;Lau, Christopher;Zaidinski, Michael;Paik, Paul K.;Zakowski, Maureen F.;Kris, Mark G.;Ladanyi, Marc

  Background: Activating mutations in the tyrosine kinase domain of HER2 (ERBB2) have been described in a subset of lung adenocarcinomas (ADCs) and are mutually exclusive with EGFR and KRAS mutations. The prevalence, clinicopathologic characteristics, prognostic implications, and molecular heterogeneity of HER2-mutated lung ADCs are not well established in US patients. Experimental Design:Lung ADC samples (n=1478) were first screened for mutations in EGFR (exons 19 and 21) and KRAS (exon 2) and negative cases were then assessed for HER2 mutations (exons 19-20) using a sizing assay and mass spectrometry. Testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1 and AKT was performed by mass spectrometry. ALK rearrangements and HER2 amplification were assessed by FISH. Results:We identified 25 cases with HER2 mutations, representing 6% of EGFR/KRAS/ALK-negative specimens. Small insertions in exon 20 accounted for 96% (24/25) of the cases. Compared to ...

  
  

Mots clés : Poumon; Biologie (Aberrations chromosomiques)

Menée à partir d'échantillons de moelle osseuse prélevés sur des patients atteints d'un myélome multiple présentant une translocation t(4;14), cette étude met en évidence le rôle joué par un petit ARN nucléolaire, ACA11, dans la prolifération cellulaire et la résistance à une chimiothérapie

• Multiple myeloma–associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress
  • The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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  Menée à partir d'échantillons de moelle osseuse prélevés sur des patients atteints d'un myélome multiple présentant une translocation t(4;14), cette étude met en évidence le rôle joué par un petit ARN nucléolaire, ACA11, dans la prolifération cellulaire et la résistance à une chimiothérapie

  “Multiple myeloma–associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress”

  • Chu, Liang;Su, Mack Y.;Maggi, Leonard B.;Lu, Lan;Mullins, Chelsea;Crosby, Seth;Huang, Gaofeng;Chng, Wee Joo;Vij, Ravi;Tomasson, Michael H.

  The histone methyltransferase WHSC1 (also known as MMSET) is overexpressed in multiple myeloma (MM) as a result of the t(4;14) chromosomal translocation and in a broad variety of other cancers by unclear mechanisms. Overexpression of WHSC1 did not transform wild-type or tumor-prone primary hematopoietic cells. We found that ACA11, an orphan box H/ACA class small nucleolar RNA (snoRNA) encoded within an intron of WHSC1, was highly expressed in t(4;14)-positive MM and other cancers. ACA11 localized to nucleoli and bound what we believe to be a novel small nuclear ribonucleoprotein (snRNP) complex composed of several proteins involved in postsplicing intron complexes. RNA targets of this uncharacterized snRNP included snoRNA intermediates hosted within ribosomal protein (RP) genes, and an RP gene signature was strongly associated with t(4;14) in patients with MM. Expression of ACA11 was sufficient to downregulate RP genes and other snoRNAs implicated in the control of oxidative stress. ...

  
  
• “Snorkeling” for missing players in cancer
  • The Journal of Clinical Investigation, sous presse, 2012 (commentaire)
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  Menée à partir d'échantillons de moelle osseuse prélevés sur des patients atteints d'un myélome multiple présentant une translocation t(4;14), cette étude met en évidence le rôle joué par un petit ARN nucléolaire, ACA11, dans la prolifération cellulaire et la résistance à une chimiothérapie

  ““Snorkeling” for missing players in cancer”

  • Riccardo Taulli ; Pier Paolo Pandolfi

  Small nucleolar RNAs (snoRNAs) are emerging as an important new class of genes deregulated in cancer. Orphans snoRNAs are encoded outside of ribosomal protein genes and are involved in either gene splicing or are microRNA precursors. In this issue of JCI, Chu et al. find that ACA11, an orphan snoRNA encoded in an intron of the WHSC1 gene, is aberrantly overexpressed in t(4;14)-positive patients with multiple myeloma (MM), in which it influences growth of MM cells, resistance to chemotherapy, and oxidative stress. These findings represent the first identification of a snoRNA overexpressed as a consequence of a chromosomal translocation, a potent driving force of the neoplastic process in general and hematopoietic malignancies in particular.

  
  

Mots clés : Myélome multiple et maladies immunoprolifératives; Biologie (Aberrations chromosomiques)

Menée sur un modèle murin, cette étude met en évidence un mécanisme de nature épigénétique par lequel une mutation du gène IDH1 est susceptible d'induire une leucémie myéloïde aiguë

• IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics
  • Nature, sous presse, 2012 (résumé)
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  Menée sur un modèle murin, cette étude met en évidence un mécanisme de nature épigénétique par lequel une mutation du gène IDH1 est susceptible d'induire une leucémie myéloïde aiguë

  “IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics”

  • Sasaki, Masato;Knobbe, Christiane B.;Munger, Joshua C.;Lind, Evan F.;Brenner, Dirk;Brustle, Anne;Harris, Isaac S.;Holmes, Roxanne;Wakeham, Andrew;Haight, Jillian;You-Ten, Annick;Li, Wanda Y.;Schalm, Stefanie;Su, Shinsam M.;Virtanen, Carl;Reifenberger, Guido;Ohashi, Pamela S.;Barber, Dwayne L.;Figueroa, Maria E.;Melnick, Ari;Zuniga-Pflucker, Juan-Carlos;Mak, Tak W.

  Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear howIDH1 andIDH2 mutationsmodifymyeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI)mice in which themost common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar ...

  
  

Mots clés : Leucémie; Biologie (Aberrations chromosomiques)

Menée sur des échantillons d'adénomes colorectaux (85 de type "plan", 35 de type "polyploïde"), cette étude met en évidence des altérations génomiques spécifiques aux adénomes plans, notamment la perte du chromosome 5q

• Chromosome 5q loss in colorectal flat adenomas
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  Menée sur des échantillons d'adénomes colorectaux (85 de type "plan", 35 de type "polyploïde"), cette étude met en évidence des altérations génomiques spécifiques aux adénomes plans, notamment la perte du chromosome 5q

  “Chromosome 5q loss in colorectal flat adenomas”

  • Voorham, Quirinus JM;Carvalho, Beatriz;Spiertz, Angela J;van Grieken, Nicole CT;Mongera, Sandra;Rondagh, Eveline J.A.;van de Wiel, Mark A.;Jordanova, Ekaterina S;Ylstra, Bauke;Kliment, Martin;Grabsch, Heike;Rembacken, Bjorn;Arai, Tomio;de Bruine, Adriaan P.;Sanduleanu, Silvia;Quirke, Philip;Mulder, Chris J.J.;van Engeland, Manon;Meijer, Gerrit A.

  Purpose Flat adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behavior compared to their polypoid counterparts. Here, we aimed to compare one of the molecular changes most explicitly associated with adenoma to carcinoma progression, i.e. chromosomal instability, between flat and polypoid colorectal adenomas. Experimental Design Consecutive series of 83 flat and 35 polypoid adenomas were analyzed for DNA copy number changes using a high-resolution arrayCGH platform, microsatellite instability (MSI) status and for mutations in the adenomatous polyposis coli (APC) gene. Immunohistochemical stainings for CD3, CD8 and FoxP3 expression were performed. Results Patterns of DNA copy number changes differed between the two phenotypes with significantly more frequent loss of 5q14.3 and 5q15-q31.1 in flat adenomas, while losses of 1p36.32-p35.3, 10q25.3, 17p12 and chromosome 18 were more frequent in polypoid adenomas (FDR less than 0.2). MSI ...

  
  

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

A partir de données portant sur 1 075 cas de cancer colorectal sans mutation du gène BRAF, cette étude compare l'association entre les mutations des codons 12 et 13 du gène KRAS et la survie des patients

• Specific Mutations in KRAS Codons 12 and 13, and Patient Prognosis in 1075 BRAF-wild-type Colorectal Cancers
  • Clinical Cancer Research, sous presse, 2012 (résumé)
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  A partir de données portant sur 1 075 cas de cancer colorectal sans mutation du gène BRAF, cette étude compare l'association entre les mutations des codons 12 et 13 du gène KRAS et la survie des patients

  “Specific Mutations in KRAS Codons 12 and 13, and Patient Prognosis in 1075 BRAF-wild-type Colorectal Cancers”

  • Imamura, Yu;Morikawa, Teppei;Liao, Xiaoyun;Lochhead, Paul;Kuchiba, Aya;Yamauchi, Mai;Qian, Zhi Rong;Nishihara, Reiko;Meyerhardt, Jeffrey;Haigis, Kevin;Fuchs, Charles S;Ogino, Shuji

  Purpose: To assess prognostic roles of various KRAS oncogene mutations in colorectal cancer, BRAF mutation status must be controlled for because BRAF mutation is associated with poor prognosis, and almost all BRAF mutants are present among KRAS-wild-type tumors. Taking into account experimental data supporting a greater oncogenic effect of codon 12 mutations compared to codon 13 mutations, we hypothesized that KRAS codon 12 mutated colorectal cancers might behave more aggressively than KRAS-wild-type tumors and codon 13 mutants. Experimental design: Utilizing molecular pathological epidemiology database of 1261 rectal and colon cancers, we examined clinical outcome and tumor biomarkers of KRAS codon 12 and 13 mutations in 1075 BRAF-wild-type cancers (i.e., controlling for BRAF status). Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for potential confounders, including stage, PIK3CA mutations, microsatellite instability, CpG island methylator ...

  
  

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

Menée sur un patient atteint d'un cancer de l'ampoule de Vater, cette étude de séquençage du génome entier identifie la présence de mutations des gènes KRAS, SMAD4 et PTEN, suggérant la mise en oeuvre d'un traitement à base d'inhibiteurs de mTOR et PI3K

• Cancer of the ampulla of Vater: analysis of the whole genome sequence exposes a potential therapeutic vulnerability
  • Genome Medicine, Vol. 4 (7), pp. 56, 2012 (article en libre accès)
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  Menée sur un patient atteint d'un cancer de l'ampoule de Vater, cette étude de séquençage du génome entier identifie la présence de mutations des gènes KRAS, SMAD4 et PTEN, suggérant la mise en oeuvre d'un traitement à base d'inhibiteurs de mTOR et PI3K

  “Cancer of the ampulla of Vater: analysis of the whole genome sequence exposes a potential therapeutic vulnerability”

  • Demeure, Michael;Craig, David;Sinari, Shripad;Moses, Tracy;Christoforides, Alexis;Dinh, Jennifer;Izatt, Tyler;Aldrich, Jessica;Decker, Ardis;Baker, Angela;Cherni, Irene;Watanabe, April;Koep, Lawrence;Lake, Douglas;Hostetter, Galen;Trent, Jeffrey;Von Hoff, Daniel;Carpten, John

  BACKGROUND:Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In rare tumors, where large-scale clinical trials are daunting, this targeted genomic approach offers a new perspective and hope for improved treatments. Cancers of the ampulla of Vater are rare tumors that comprise only about 0.2% of gastrointestinal cancers. Consequently, they are often treated as either distal common bile duct or pancreatic cancers.METHODS:We analyzed a DNA from a resected cancer of the ampulla of Vater and whole blood DNA, from a 63 year-old man who underwent a pancreaticoduodenectomy, by whole genome sequencing achieving 37 and 40x coverage respectively. We determined somatic mutations and structural alterations.RESULTS:We identified relevant aberrations including deleterious mutations of KRAS and SMAD4 as well as a homozygous focal deletion of the PTEN tumor suppressor gene. These findings suggest that these tumors have a ...

  
  

Mots clés : Appareil digestif (autre); Biologie (Aberrations chromosomiques)

Cet article passe en revue les travaux récents allant à l'encontre du modèle dominant selon lequel l'accumulation de mutations oncogéniques explique la relation entre âge et incidence des cancers

• Challenging the axiom: does the occurrence of oncogenic mutations truly limit cancer development with age[quest]
  • Oncogene, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents allant à l'encontre du modèle dominant selon lequel l'accumulation de mutations oncogéniques explique la relation entre âge et incidence des cancers

  “Challenging the axiom: does the occurrence of oncogenic mutations truly limit cancer development with age[quest]”

  • DeGregori, J.

  A widely accepted paradigm in cancer research holds that the development of cancers is rate limited by the occurrence of oncogenic mutations. In particular, the exponential rise in the incidence of most cancers with age is thought to reflect the time required for cells to accumulate the multiple oncogenic mutations needed to confer the cancer phenotype. Here I will argue against the axiom that the occurrence of oncogenic mutations limits cancer incidence with age, based on several observations, including that the rate of mutation accumulation is maximal during ontogeny, oncogenic mutations are frequently detected in normal tissues, the evolution of complex multicellularity was not accompanied by reductions in mutation rates, and that many oncogenic mutations have been shown to impair stem cell activity. Moreover, although evidence that has been used to support the current paradigm includes increased cancer incidence in individuals with inherited DNA repair deficiencies or exposed to ...

  
  

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

Cet article passe en revue les travaux récents sur le rôle des mécanismes épigénétiques dans les cancers

• Cancer Epigenetics: From Mechanism to Therapy
  • Cell, Vol. 150 (1), pp. 12-27, 2012 (article en libre accès)
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  Cet article passe en revue les travaux récents sur le rôle des mécanismes épigénétiques dans les cancers

  “Cancer Epigenetics: From Mechanism to Therapy”

  • Dawson, Mark A;Kouzarides, Tony

  The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer.

  
  

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

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme de coopération entre les voies de signalisation JNK et PTEN pour réguler la progression d'une néoplasie de la prostate vers un adénocarcinome invasif

• JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme de coopération entre les voies de signalisation JNK et PTEN pour réguler la progression d'une néoplasie de la prostate vers un adénocarcinome invasif

  “JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate”

  • Hübner, Anette;Mulholland, David J.;Standen, Claire L.;Karasarides, Maria;Cavanagh-Kyros, Julie;Barrett, Tamera;Chi, Hongbo;Greiner, Dale L.;Tournier, Cathy;Sawyers, Charles L.;Flavell, Richard A.;Wu, Hong;Davis, Roger J.

  The c-Jun NH2-terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) conditional deletion model of prostate cancer. Mice with JNK deficiency in the prostate epithelium (ΔJnk ΔPten mice) develop androgen-independent metastatic prostate cancer more rapidly than control (ΔPten) mice. Similarly, prevention of JNK activation in the prostate epithelium (ΔMkk4 ΔMkk7 ΔPten mice) causes rapid development of invasive adenocarcinoma. We found that JNK signaling defects cause an androgen-independent expansion of the immature progenitor cell population in the primary tumor. The JNK-deficient progenitor cells display increased proliferation and tumorigenic potential compared with progenitor cells from control prostate tumors. These data demonstrate that the JNK and PTEN ...

  
  

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

Menée sur un modèle murin, cette étude met en évidence le rôle joué par Sox10 dans la formation d'un naevus congénital géant et d'un mélanome

• Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma
  • Nature Cell Biology, sous presse, 2012 (résumé)
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  Menée sur un modèle murin, cette étude met en évidence le rôle joué par Sox10 dans la formation d'un naevus congénital géant et d'un mélanome

  “Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma”

  • Shakhova, Olga;Zingg, Daniel;Schaefer, Simon M.;Hari, Lisette;Civenni, Gianluca;Blunschi, Jacqueline;Claudinot, Stephanie;Okoniewski, Michal;Beermann, Friedrich;Mihic-Probst, Daniela;Moch, Holger;Wegner, Michael;Dummer, Reinhard;Barrandon, Yann;Cinelli, Paolo;Sommer, Lukas

  Giant congenital naevi are pigmented childhood lesions that frequently lead to melanoma, the most aggressive skin cancer. The mechanisms underlying this malignancy are largely unknown, and there are no effective therapies. Here we describe a mouse model for giant congenital naevi and show that naevi and melanoma prominently express Sox10,…

  
  

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

Menée sur des lignées cellulaires de mélanome, cette étude met en évidence des mécanismes de régulation d'un réseau de micro-ARNs par la voie de signalisation B-Raf, qui est notamment activée par la mutation B-RafV600E

• Oncogenic B-Raf signaling in melanoma cells controls a network of microRNAs with combinatorial functions
  • Oncogene, sous presse, 2012 (résumé)
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  Menée sur des lignées cellulaires de mélanome, cette étude met en évidence des mécanismes de régulation d'un réseau de micro-ARNs par la voie de signalisation B-Raf, qui est notamment activée par la mutation B-RafV600E

  “Oncogenic B-Raf signaling in melanoma cells controls a network of microRNAs with combinatorial functions”

  • Couts, K. L.;Anderson, E. M.;Gross, M. M.;Sullivan, K.;Ahn, N. G.

  Over two-thirds of melanomas have activating mutations in B-Raf, leading to constitutive activation of the B-Raf/MKK/ERK signaling pathway. The most prevalent mutation, B-RafV600E, promotes cancer cell behavior through mechanisms that are still incompletely defined. Here, we used a sensitive microarray profiling platform to compare microRNA (miRNA) expression levels between primary melanocytes and B-RafV600E-positive melanoma cell lines, and between melanoma cells treated in the presence and absence of an MKK1/2 inhibitor. We identified a network of >20 miRNAs deregulated by B-Raf/MKK/ERK in melanoma cells, the majority of which modulate the expression of key cancer regulatory genes and functions. Importantly, miRNAs within the network converge on protein regulation and cancer phenotypes, suggesting that these miRNAs might function combinatorially. We show that miRNAs augment effects on protein repression and cell invasion when co-expressed, and gene-specific latency and interference ...

  
  

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

Cet article passe en revue les travaux récents sur le rôle de certains micro-ARNs dans les lymphomes à cellules B

• The role of miRNAs in the pathogenesis and diagnosis of B-cell lymphomas
  • Blood, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur le rôle de certains micro-ARNs dans les lymphomes à cellules B

  “The role of miRNAs in the pathogenesis and diagnosis of B-cell lymphomas”

  • Di Lisio, Lorena;Martinez, Nerea;Montes-Moreno, Santiago;Piris-Villaespesa, Miguel;Sanchez-Beato, Margarita;Piris, Miguel A.

  There is a demand to understand B-cell lymphoma pathogenesis better, to identify new markers and to define multiple lymphoproliferative disorders more accurately. MiRNAs are regulators of protein translation, comprising a group of more than 1500 short non-coding single-strand RNA molecules of about 22 nucleotides in length. They are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum. Expression of individual miRNAs and miRNA signatures allows specific cell-differentiation stages to be identified, and is a powerful diagnostic and prognostic method. Here we review what is known about the pathogenic relevance of miRNAs, and use of miRNAs for the diagnosis and prognosis of B-cell lymphomas. Most of the published data concern chronic lymphocytic lymphoma and diffuse large B-cell lymphoma, and implicate miRNAs in the pathogenesis of these diseases. They identify miRNAs that could be used for diagnosis, prognosis or prediction of response to specific therapies.

  
  

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

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel des cellules souches du mésenchyme, via la production de prostaglandine E2 et de diverses cytokines, induisent la formation d'une niche de cellules souches cancéreuses

• Cancer-stimulated mesenchymal stem cells create a carcinoma stem-cell niche via Prostaglandin E2 signaling
  • Cancer Discovery, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel des cellules souches du mésenchyme, via la production de prostaglandine E2 et de diverses cytokines, induisent la formation d'une niche de cellules souches cancéreuses

  “Cancer-stimulated mesenchymal stem cells create a carcinoma stem-cell niche via Prostaglandin E2 signaling”

  • Li, Hua-Jung;Reinhardt, Ferenc;Herschman, Harvey R.;Weinberg, Robert A

  Mesenchymal cells of the tumor-associated stroma are critical determinants of carcinoma cell behavior. We focus here on interactions of carcinoma cells with mesenchymal stem cells (MSCs), which are recruited to the tumor stroma and, once present, are able to influence the phenotype of the carcinoma cells. We find that carcinoma cell-derived interleukin-1 (IL-1) induces prostaglandin E2 (PGE2) secretion by MSCs. The resulting PGE2 operates in an autocrine manner, cooperating with ongoing paracrine IL-1 signaling, to induce expression of a group of cytokines by the MSCs. The PGE2 and cytokines then proceed to act in a paracrine fashion on the carcinoma cells to induce activation of β-catenin signaling and formation of cancer stem cells. These observations indicate that MSCs and derived cell types create a cancer stem-cell niche to enable tumor progression via release of PGE2 and cytokines.

  
  

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

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine SHARP1 régule les processus invasif et métastatique d'un cancer du sein triplement négatif

• SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors
  • Nature, sous presse, 2012 (résumé)
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  Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine SHARP1 régule les processus invasif et métastatique d'un cancer du sein triplement négatif

  “SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors”

  • Montagner, Marco;Enzo, Elena;Forcato, Mattia;Zanconato, Francesca;Parenti, Anna;Rampazzo, Elena;Basso, Giuseppe;Leo, Genesio;Rosato, Antonio;Bicciato, Silvio;Cordenonsi, Michelangelo;Piccolo, Stefano

  The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1 α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel –Lindau tumour suppressor), hypoxia and the ...

  
  

Mots clés : Sein; Biologie (Progression et métastases)

Menée sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein (53 carcinomes canalaires in situ et 52 cancers invasifs) et à l'aide de xénogreffes, cette étude identifie des profils d'expression de gènes spécifiques des carcinomes in situ et invasif

• Differentially Expressed Genes Regulating the Progression of Ductal Carcinoma in Situ to Invasive Breast Cancer
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein (53 carcinomes canalaires in situ et 52 cancers invasifs) et à l'aide de xénogreffes, cette étude identifie des profils d'expression de gènes spécifiques des carcinomes in situ et invasif

  “Differentially Expressed Genes Regulating the Progression of Ductal Carcinoma in Situ to Invasive Breast Cancer”

  • Lee, Sangjun;Stewart, Sheila;Nagtegaal, Iris;Luo, Jingqin;Wu, Yun;Colditz, Graham;Medina, Dan;Allred, D Craig

  Molecular mechanisms mediating the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) remain largely unknown. We used gene expression profiling of human DCIS (n=53) and IBC (n=51) to discover uniquely expressed genes that may also regulate progression. There were 470 total differentially expressed genes (≥ 2 fold; p<0.05). Elevated expression of genes involved in synthesis and organization of extracellular matrix was particularly prominent in the epithelium of IBC. The degree of overlap of the genes with nine similar studies in the literature was determined to help prioritize their potential importance, resulting in 74 showing overlap in ≥ 2 studies (average 3.6 studies/gene; range 2-8 studies). Using hierarchical clustering, the 74-gene profile was able to correctly categorize 96%, 93%, and 85% of samples in this study and two similar independent studies, respectively. To study the progression of DCIS to IBC in vivo, we introduced human DCIS cell lines ...

  
  

Mots clés : Sein; Biologie (Progression et métastases)

Menée sur un modèle murin, cette étude suggère que le développement d'un cancer du sein serait le résultat d'un processus métastatique émanant d'une tumeur rénale

• Metastatic view of breast cancer
  • Cancer and Metastasis Reviews, sous presse, 2012 (résumé)
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  Menée sur un modèle murin, cette étude suggère que le développement d'un cancer du sein serait le résultat d'un processus métastatique émanant d'une tumeur rénale

  “Metastatic view of breast cancer”

  • Banfalvi, Gaspar

  The ancient view regarding breast cancer as a metastasis has not been supported so far by experimental evidence. We have implanted nephroblastoma tumor cells resulting in a rat metastatic kidney capsule–parathymic lymph node (PTN) model. India ink implantation confirmed the lymphatic connection between the primary tumor of the kidney and PTNs. 18 F-FDG glucose analog distribution provided further evidence that the first metastatic sites of distant tumor progression are PTNs. Tumor invasion caused disruptions in the tissue of the primary renal tumor, releasing cancer cells into the peritoneal cavity. Colloidal particles, among them bacteria and India ink, crossed transdiaphragmatic channels drained from the peritonel cavity to the thoracic lymphatics and entered not only in the parathymic lymph nodes but also in the anterior mammary lymph nodes. The kidney capsule–PTN complex is reflecting a so far unknown mechanism of tumor development and suggests a similar tumor progression ...

  
  

Mots clés : Sein; Biologie (Progression et métastases)

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la voie de signalisation de la chimiokine CXCL1 dans le processus métastatique d'un cancer du sein et la résistance thérapeutique

• A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis
  • Cell, Vol. 150 (1), pp. 165-178, 2012 (résumé)
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  Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la voie de signalisation de la chimiokine CXCL1 dans le processus métastatique d'un cancer du sein et la résistance thérapeutique

  “A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis”

  • Acharyya, Swarnali;Oskarsson, Thordur;Vanharanta, Sakari;Malladi, Srinivas;Kim, Juliet;Morris, Patrick G;Manova-Todorova, Katia;Leversha, Margaret;Hogg, Nancy;Seshan, Venkatraman E;Norton, Larry;Brogi, Edi;Massagué, Joan

  Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b+Gr1+ myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-± production by endothelial and other stromal cells. TNF-± via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of ...

  
  

Mots clés : Sein; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur le rôle des cellules souches rénales dans les carcinomes à cellules rénales

• Renal stem cells and their implications for kidney cancer
  • Seminars in Cancer Biology, sous presse, 2012 (résumé)
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  Cet article passe en revue les travaux récents sur le rôle des cellules souches rénales dans les carcinomes à cellules rénales

  “Renal stem cells and their implications for kidney cancer”

  • Axelson, Håkan;Johansson, Martin E.

  The renal cell carcinomas (RCC) denote a diverse set of neoplasias with unique genetic and histological features. The RCCs emanate from the renal tubule, a highly heterogeneous epithelial structure, and depending on which cell is malignified the resulting cancer displays unique characteristics. Notwithstanding this, the cells of origin for the RCC forms are far from established, and only inferred by the accumulated weight of marker similarities, not always providing an unequivocal picture. The tubular epithelium is normally mitotically quiescent, but demonstrates a considerable regenerative capacity upon renal injury. Recently the hypothesis that regeneration is driven by adult stem cells has been added experimental support, providing further complexity to the issue of renal carcinogenesis. Whether these cells are linked to RCC is an open question. In the present review we therefore present the prevailing theories regarding kidney regeneration, since a better understanding of this ...

  
  

Mots clés : Rein; Biologie (Progression et métastases)

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel l'interleukine 9, produite par des lymphocytes T, régule la réponse immunitaire dans les mélanomes

• Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells
  • Nature Medicine, sous presse, 2012 (résumé)
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  Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel l'interleukine 9, produite par des lymphocytes T, régule la réponse immunitaire dans les mélanomes

  “Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells”

  • Purwar, Rahul;Schlapbach, Christoph;Xiao, Sheng;Kang, Hong Soon;Elyaman, Wassim;Jiang, Xiaodong;Jetten, Anton M.;Khoury, Samia J.;Fuhlbrigge, Robert C.;Kuchroo, Vijay K.;Clark, Rachael A.;Kupper, Thomas S.

  Interleukin-9 (IL-9) is a T cell cytokine that acts through a γC-family receptor on target cells and is associated with inflammation and allergy. We determined that T cells from mice deficient in the T helper type 17 (TH17) pathway genes encoding retinoid-related orphan receptor γ (ROR-γ) and IL-23 receptor (IL-23R) produced abundant IL-9, and we found substantial growth inhibition of B16F10 melanoma in these mice. IL-9 –blocking antibodies reversed this tumor growth inhibition and enhanced tumor growth in wild-type (WT) mice. Il9r−/− mice showed accelerated tumor growth, and administration of recombinant IL-9 (rIL-9) to tumor-bearing WT and Rag1−/− mice inhibited melanoma as well as lung carcinoma growth. Adoptive transfer of tumor-antigen–specific TH9 cells into both WT and Rag1−/− mice suppressed melanoma growth; this effect was abrogated by treatment with neutralizing antibodies to IL-9. Exogenous rIL-9 inhibited tumor growth in Rag1−/− mice but not in ...

  
  

Mots clés : Mélanome; Biologie (Progression et métastases)

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la bêta-arrestine 2 dans le déclenchement et la progression d'une leucémie myéloïde chronique

• β-Arrestin2 mediates the initiation and progression of myeloid leukemia
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la bêta-arrestine 2 dans le déclenchement et la progression d'une leucémie myéloïde chronique

  “β-Arrestin2 mediates the initiation and progression of myeloid leukemia”

  • Fereshteh, Mark;Ito, Takahiro;Kovacs, Jeffrey J.;Zhao, Chen;Kwon, Hyog Young;Tornini, Valerie;Konuma, Takaaki;Chen, Minyong;Lefkowitz, Robert J.;Reya, Tannishtha

  β-Arrestins were initially discovered as negative regulators of G protein-coupled receptor signaling. Although β-arrestins have more recently been implicated as scaffold proteins that interact with various mitogenic and developmental signals, the genetic role of β-arrestins in driving oncogenesis is not known. Here we have investigated the role of β-arrestin in hematologic malignancies and have found that although both β-arrestin1 and -2 are expressed in the hematopoietic system, loss of β-arrestin2 preferentially leads to a severe impairment in the establishment and propagation of the chronic and blast crisis phases of chronic myelogenous leukemia (CML). These defects are linked to a reduced frequency, as well as defective self-renewal capacity of the cancer stem-cell population, in mouse models and in human CML patient samples. At a molecular level, the loss of β-arrestin2 leads to a significant inhibition of β-catenin stabilization, and ectopic activation of Wnt signaling ...

  
  

Mots clés : Leucémie; Biologie (Progression et métastases)

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en interagissant avec les cellules tumorales circulantes, les neutrophiles favorisent la formation de métastases hépatiques

• Neutrophils promote liver metastasis via Mac-1 mediated interactions with circulating tumor cells
  • Cancer Research, sous presse, 2012 (résumé)
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  Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en interagissant avec les cellules tumorales circulantes, les neutrophiles favorisent la formation de métastases hépatiques

  “Neutrophils promote liver metastasis via Mac-1 mediated interactions with circulating tumor cells”

  • Spicer, Jonathan D.;McDonald, Braedon;Cools-Lartigue, Jonathan J.;Chow, Simon C.;Giannias, Betty;Kubes, Paul;Ferri, Lorenzo E.

  Although circulating neutrophils are associated with distant metastasis and poor outcome in a number of epithelial malignancies, whether neutrophils play an active causal role in the metastatic cascade remains unclear. Using in vivo models of metastasis, we found that neutrophils promote cancer cell adhesion within liver sinusoids and thereby influence metastasis. Neutrophil depletion prior to cancer cell inoculation resulted in a decreased number of gross metastases in an intra-splenic model of liver metastasis. This effect was reversed when inflamed neutrophils were co-inoculated with cancer cells. In addition, early adhesion within liver sinusoids was inhibited in the absence of neutrophils and partially restored with a short perfusion of isolated activated neutrophils. Intra-vital microscopy showed that cancer cells adhered directly on top of arrested neutrophils, suggesting that neutrophils may act as a bridge to facilitate interactions between cancer cells and the liver ...

  
  

Mots clés : Foie; Biologie (Progression et métastases)

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel deux micro-ARNs secrétés par une tumeur, miR-21 et miR-29a, induisent une réponse inflammatoire favorisant le processus métastatique

• MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response
  • Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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  Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel deux micro-ARNs secrétés par une tumeur, miR-21 et miR-29a, induisent une réponse inflammatoire favorisant le processus métastatique

  “MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response”

  • Fabbri, Muller;Paone, Alessio;Calore, Federica;Galli, Roberta;Gaudio, Eugenio;Santhanam, Ramasamy;Lovat, Francesca;Fadda, Paolo;Mao, Charlene;Nuovo, Gerard J.;Zanesi, Nicola;Crawford, Melissa;Ozer, Gulcin H.;Wernicke, Dorothee;Alder, Hansjuerg;Caligiuri, Michael A.;Nana-Sinkam, Patrick;Perrotti, Danilo;Croce, Carlo M.

  MicroRNAs (miRNAs) are small noncoding RNAs, 19–24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs. Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is implicated in tumor–immune system communication ...

  
  

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

Cette étude présente une nouvelle méthode pour corriger les erreurs de lecture de l'ADN produites par des machines de séquençage "molécule unique"

• Hybrid error correction and de novo assembly of single-molecule sequencing reads
  • Nature Biotechnology, sous presse, 2012 (résumé)
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  Cette étude présente une nouvelle méthode pour corriger les erreurs de lecture de l'ADN produites par des machines de séquençage "molécule unique"

  “Hybrid error correction and de novo assembly of single-molecule sequencing reads”

  • Koren, Sergey;Schatz, Michael C.;Walenz, Brian P.;Martin, Jeffrey;Howard, Jason T.;Ganapathy, Ganeshkumar;Wang, Zhong;Rasko, David A.;McCombie, W. Richard;Jarvis, Erich D.;Phillippy, Adam M.

  Single-molecule sequencing instruments can generate multikilobase sequences with the potential to greatly improve genome and transcriptome assembly. However, the error rates of single-molecule reads are high, which has limited their use thus far to resequencing bacteria. To address this limitation, we introduce a correction algorithm and assembly strategy that uses short, high-fidelity sequences to correct the error in single-molecule sequences. We demonstrate the utility of this approach on reads generated by a PacBio RS instrument from phage, prokaryotic and eukaryotic whole genomes, including the previously unsequenced genome of the parrot Melopsittacus undulatus, as well as for RNA-Seq reads of the corn (Zea mays) transcriptome. Our long-read correction achieves >99.9% base-call accuracy, leading to substantially better assemblies than current sequencing strategies: in the best example, the median contig size was quintupled relative to high-coverage, second-generation assemblies. ...

  
  

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