Accueil Nota Bene Cancer V2 Numéro 124 du 21 Février 2012 Biologie

Nota Bene Cancer Numéro 124 du 21 Février 2012

Biologie

Aberrations chromosomiques

Menée sur des échantillons tumoraux prélevés sur des modèles murins et des patients atteints de médulloblastome, cette étude analyse les différences dans les mutations observées au sein des tumeurs primitives et de leurs métastases

Clonal selection drives genetic divergence of metastatic medulloblastoma
• Nature, sous presse, 2012 (résumé)

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Menée sur des échantillons tumoraux prélevés sur des modèles murins et des patients atteints de médulloblastome, cette étude analyse les différences dans les mutations observées au sein des tumeurs primitives et de leurs métastases

“Clonal selection drives genetic divergence of metastatic medulloblastoma”

• Wu, Xiaochong;Northcott, Paul A.;Dubuc, Adrian;Dupuy, Adam J.;Shih, David J. H.;Witt, Hendrik;Croul, Sidney;Bouffet, Eric;Fults, Daniel W.;Eberhart, Charles G.;Garzia, Livia;Van Meter, Timothy;Zagzag, David;Jabado, Nada;Schwartzentruber, Jeremy;Majewski, Jacek;Scheetz, Todd E.;Pfister, Stefan M.;Korshunov, Andrey;Li, Xiao-Nan;Scherer, Stephen W.;Cho, Yoon-Jae;Akagi, Keiko;MacDonald, Tobey J.;Koster, Jan;McCabe, Martin G.;Sarver, Aaron L.;Collins, V. Peter;Weiss, William A.;Largaespada, David A.;Collier, Lara S.;Taylor, Michael D.

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted ...
Cancer genetics: Evolution after tumour spread
• Nature, sous presse, 2012 (commentaire)

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Menée sur des échantillons tumoraux prélevés sur des modèles murins et des patients atteints de médulloblastome, cette étude analyse les différences dans les mutations observées au sein des tumeurs primitives et de leurs métastases

“Cancer genetics: Evolution after tumour spread”

• Clifford, Steven C.

A genetic study of brain cancers in mice and humans reveals distinct mutations in primary tumours and their metastases, suggesting that the two disease 'compartments' may require different treatments.

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

Ces trois études mettent en évidence des mécanismes par lesquels des mutations du gène IDH1 participent à la formation d'un gliome ou d'une leucémie

IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
• Nature, sous presse, 2012 (résumé)

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Ces trois études mettent en évidence des mécanismes par lesquels des mutations du gène IDH1 participent à la formation d'un gliome ou d'une leucémie

“IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype”

• Turcan, Sevin;Rohle, Daniel;Goenka, Anuj;Walsh, Logan A.;Fang, Fang;Yilmaz, Emrullah;Campos, Carl;Fabius, Armida W. M.;Lu, Chao;Ward, Patrick S.;Thompson, Craig B.;Kaufman, Andrew;Guryanova, Olga;Levine, Ross;Heguy, Adriana;Viale, Agnes;Morris, Luc G. T.;Huse, Jason T.;Mellinghoff, Ingo K.;Chan, Timothy A.

Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and ...
IDH mutation impairs histone demethylation and results in a block to cell differentiation
• Nature, sous presse, 2012 (résumé)

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Ces trois études mettent en évidence des mécanismes par lesquels des mutations du gène IDH1 participent à la formation d'un gliome ou d'une leucémie

“IDH mutation impairs histone demethylation and results in a block to cell differentiation”

• Lu, Chao ; Ward, Patrick S. ; Kapoor, Gurpreet S. ; Rohle, Dan ; Turcan, Sevin ; Abdel-Wahab, Omar ; Edwards, Christopher R. ; Khanin, Raya ; Figueroa, Maria E. ; Melnick, Ari ; Wellen, Kathryn E. ; O/'Rourke, Donald M. ; Berger, Shelley L. ; Chan, Timothy A. ; Levine, Ross L. ; Mellinghoff, Ingo K. ; Thompson, Craig B.

Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the ...
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
• Nature, sous presse, 2012 (résumé)

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Ces trois études mettent en évidence des mécanismes par lesquels des mutations du gène IDH1 participent à la formation d'un gliome ou d'une leucémie

“Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation”

• Koivunen, Peppi ; Lee, Sungwoo ; Duncan, Christopher G. ; Lopez, Giselle ; Lu, Gang ; Ramkissoon, Shakti ; Losman, Julie A. ; Joensuu, Paivi ; Bergmann, Ulrich ; Gross, Stefan ; Travins, Jeremy ; Weiss, Samuel ; Looper, Ryan ; Ligon, Keith L. ; Verhaak, Roel G. W. ; Yan, Hai ; Kaelin, William G.

The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumours but can suppress tumour growth in some other contexts. IDH1 and IDH2, which catalyse the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumours and leukaemias. The resulting mutants have the neomorphic ability to convert 2-OG to the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). Here we show that (R)-2HG, but not ...

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

Menée sur des échantillons de tissus sains et de tumeurs prélevés sur 55 patients atteints d'un lymphome diffus à grandes cellules B, cette étude de séquençage des exons identifie les principales mutations somatiques impliquées dans la pathogenèse de cette forme de lymphome

Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing
• Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)

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Menée sur des échantillons de tissus sains et de tumeurs prélevés sur 55 patients atteints d'un lymphome diffus à grandes cellules B, cette étude de séquençage des exons identifie les principales mutations somatiques impliquées dans la pathogenèse de cette forme de lymphome

“Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing”

• Lohr, Jens G.;Stojanov, Petar;Lawrence, Michael S.;Auclair, Daniel;Chapuy, Bjoern;Sougnez, Carrie;Cruz-Gordillo, Peter;Knoechel, Birgit;Asmann, Yan W.;Slager, Susan L.;Novak, Anne J.;Dogan, Ahmet;Ansell, Stephen M.;Link, Brian K.;Zou, Lihua;Gould, Joshua;Saksena, Gordon;Stransky, Nicolas;Rangel-Escareño, Claudia;Fernandez-Lopez, Juan Carlos;Hidalgo-Miranda, Alfredo;Melendez-Zajgla, Jorge;Hernández-Lemus, Enrique;Schwarz-Cruz y Celis, Angela;Imaz-Rosshandler, Ivan;Ojesina, Akinyemi I.;Jung, Joonil;Pedamallu, Chandra S.;Lander, Eric S.;Habermann, Thomas M.;Cerhan, James R.;Shipp, Margaret A.;Getz, Gad;Golub, Todd R.

To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase–mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are ...

Mots clés : Lymphome; Biologie (Aberrations chromosomiques)

Menée sur des échantillons de tumeurs et de tissus sains prélevés sur 4 patients atteints d'un carcinome hépatocellulaire, cette étude identifie les perturbations génomiques associées à 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 des échantillons de tumeurs et de tissus sains prélevés sur 4 patients atteints d'un carcinome hépatocellulaire, cette étude identifie les perturbations génomiques associées à 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 nontumor genomes (>80× coverage) and transcriptomes of four HCC patients and identified 255 HBV integration sites. Increased sequencing to 240× 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)

Cet article passe en revue les travaux récents adoptant une perspective évolutionniste pour étudier les génomes des cancers

Evolution of the cancer genome
• Trends in Genetics, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents adoptant une perspective évolutionniste pour étudier les génomes des cancers

“Evolution of the cancer genome”

• Podlaha, Ondrej;Riester, Markus;De, Subhajyoti;Michor, Franziska

Human tumors result from an evolutionary process operating on somatic cells within tissues, whereby natural selection operates on the phenotypic variability generated by the accumulation of genetic, genomic and epigenetic alterations. This somatic evolution leads to adaptations such as increased proliferative, angiogenic, and invasive phenotypes. In this review we outline how cancer genomes are beginning to be investigated from an evolutionary perspective. We describe recent progress in the cataloging of somatic genetic and genomic alterations, and investigate the contributions of germline as well as epigenetic factors to cancer genome evolution. Finally, we outline the challenges facing researchers who investigate the processes driving the evolution of the cancer genome.

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

Oncogènes et suppresseurs de tumeurs

Menée sur un modèle murin de gliome, cette étude caractérise le réseau de signalisation organisé autour de l'oncogène IGFBP2

Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-κB network
• Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)

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Menée sur un modèle murin de gliome, cette étude caractérise le réseau de signalisation organisé autour de l'oncogène IGFBP2

“Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-κB network”

• Holmes, Kristen M.;Annala, Matti;Chua, Corrine Y. X.;Dunlap, Sarah M.;Liu, Yuexin;Hugen, Niek;Moore, Lynette M.;Cogdell, David;Hu, Limei;Nykter, Matti;Hess, Kenneth;Fuller, Gregory N.;Zhang, Wei

Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication-competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin β1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this ...

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

Menée in vitro et sur un modèle murin, cette étude met en évidence le rôle joué par une enzyme, USP15 , dans la régulation de la voie de signalisation du facteur de croissance TGF-β et la pathogenèse d'un glioblastome

USP15 stabilizes
• Nature Medicine, sous presse, 2012 (résumé)

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Menée in vitro et sur un modèle murin, cette étude met en évidence le rôle joué par une enzyme, USP15 , dans la régulation de la voie de signalisation du facteur de croissance TGF-β et la pathogenèse d'un glioblastome

“USP15 stabilizes ”

• Eichhorn, Pieter J. A.;Rodon, Laura;Gonzalez-Junca, Alba;Dirac, Annette;Gili, Magui;Martinez-Saez, Elena;Aura, Claudia;Barba, Ignasi;Peg, Vicente;Prat, Aleix;Cuartas, Isabel;Jimenez, Jose;Garcia-Dorado, David;Sahuquillo, Juan;Bernards, Rene;Baselga, Jose;Seoane, Joan

In advanced cancer, including glioblastoma, the transforming growth factor β (TGF-β) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-β signaling pathway. USP15 binds to the SMAD7 –SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF- β receptor (TβR-I), leading to an enhanced TGF-β signal. High expression of USP15 correlates with high TGF-β activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the ...

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

Menée sur un modèle murin de tumeurs malignes des enveloppes des nerfs périphériques, cette étude évalue la proportion de cellules tumorales dotées d'une capacité à former de nouvelles tumeurs

Tumorigenic Cells Are Common in Mouse MPNSTs but Their Frequency Depends upon Tumor Genotype and Assay Conditions
• Cancer cell, Vol. 21 (2), pp. 240-252, 2012 (résumé)

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Menée sur un modèle murin de tumeurs malignes des enveloppes des nerfs périphériques, cette étude évalue la proportion de cellules tumorales dotées d'une capacité à former de nouvelles tumeurs

“Tumorigenic Cells Are Common in Mouse MPNSTs but Their Frequency Depends upon Tumor Genotype and Assay Conditions”

• Buchstaller, Johanna;McKeever, Paul E;Morrison, Sean J

Tumor-initiating cells have been suggested to be rare in many cancers. We tested this in mouse malignant peripheral nerve sheath tumors (MPNSTs) and found that 18% of primary and 49% of passaged MPNST cells from Nf1+/ ; Ink4a/Arf / mice formed tumors upon transplantation, whereas only 1.8% to 2.6% of MPNST cells from Nf1+/ ; p53+/ mice did. MPNST cells of both genotypes require laminin binding to ²1-integrin for clonogenic growth. Most MPNST cells from Nf1+/ ; Ink4a/Arf / mice expressed laminin, whereas most MPNST cells from Nf1+/ ; p53+/ mice did not. Exogenous laminin increased the percentage of MPNST cells from Nf1+/ ; p53+/ but not Nf1+/ ; Ink4a/Arf / mice that formed tumorigenic colonies. Tumor-forming potential is common among MPNST cells, but the assay conditions required to detect it vary with tumor genotype. º Many MPNST cells have the potential to form tumors º Some sarcomas contain high frequencies of tumor-initiating cells º Tumors of different genotypes require ...

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

Menée sur un modèle murin, cette étude suggère que l'origine d'un cancer séreux de l'ovaire de haut grade réside dans la trompe de Fallope

High-grade serous ovarian cancer arises from fallopian tube in a mouse model
• Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)

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Menée sur un modèle murin, cette étude suggère que l'origine d'un cancer séreux de l'ovaire de haut grade réside dans la trompe de Fallope

“High-grade serous ovarian cancer arises from fallopian tube in a mouse model”

• Kim, Jaeyeon;Coffey, Donna M.;Creighton, Chad J.;Yu, Zhifeng;Hawkins, Shannon M.;Matzuk, Martin M.

Although ovarian cancer is the most lethal gynecologic malignancy in women, little is known about how the cancer initiates and metastasizes. In the last decade, new evidence has challenged the dogma that the ovary is the main source of this cancer. The fallopian tube has been proposed instead as the primary origin of high-grade serous ovarian cancer, the subtype causing 70% of ovarian cancer deaths. By conditionally deleting Dicer, an essential gene for microRNA synthesis, and Pten, a key negative regulator of the PI3K pathway, we show that high-grade serous carcinomas arise from the fallopian tube in mice. In these Dicer-Pten double-knockout mice, primary fallopian tube tumors spread to engulf the ovary and then aggressively metastasize throughout the abdominal cavity, causing ascites and killing 100% of the mice by 13 mo. Besides the clinical resemblance to human serous cancers, these fallopian tube cancers highly express genes that are known to be up-regulated in human serous ...

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

Menée in vitro, cette étude suggère que le facteur de transcription FOXO1 joue un rôle de suppresseur de tumeurs dans le lymphome de Hodgkin classique

FOXO1 is a tumor suppressor in classical Hodgkin lymphoma
• Blood, sous presse, 2012 (résumé)

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Menée in vitro, cette étude suggère que le facteur de transcription FOXO1 joue un rôle de suppresseur de tumeurs dans le lymphome de Hodgkin classique

“FOXO1 is a tumor suppressor in classical Hodgkin lymphoma”

• Xie, Linka;Ushmorov, Alexey;Leithäuser, Frank;Guan, Hanfeng;Steidl, Christian;Färbinger, Johanna;Pelzer, Christin;Vogel, Marion J.;Maier, Harald J.;Gascoyne, Randy D.;Möller, Peter;Wirth, Thomas

The FOXO transcription factors control proliferation and apoptosis in different cell types. Their activity is regulated by posttranslational modifications, mainly by the PI3K-PKB pathway, which controls nuclear export and degradation. We show that FOXO1 is highly expressed in normal germinal center (GC) B cells as well as in non-Hodgkin lymphomas (NHL) including follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mucosa-associated lymphoid tissue non-Hodgkin lymphoma (MALT-NHL), B cell chronic lymphocytic leukemia (B-CLL), and mantle-cell lymphoma (MCL). In contrast, in 31 out of 32 classical Hodgkin lymphoma (cHL) cases, Hodgkin and Reed-Sternberg (HRS) cells were FOXO1 negative. Neoplastic cells of nodular lymphocyte predominant Hodgkin lymphoma (LPHL) were negative in 14 out of 20 cases. FOXO1 was down-regulated in cHL cell lines while it was expressed in NHL cell lines at levels comparable to normal B cells. Ectopic expression of a constitutively active FOXO1 induced ...

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

Menée in vitro et in vivo, cette étude met en évidence le rôle d'une sérine-thréonine protéine kinase, GSK-3α, dans le développement d'une léucémie myéloïde aiguë

The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia
• The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)

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Menée in vitro et in vivo, cette étude met en évidence le rôle d'une sérine-thréonine protéine kinase, GSK-3α, dans le développement d'une léucémie myéloïde aiguë

“The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia”

• Banerji, Versha;Frumm, Stacey M.;Ross, Kenneth N.;Li, Loretta S.;Schinzel, Anna C.;Hahn, Cynthia K.;Kakoza, Rose M.;Chow, Kwan T.;Ross, Linda;Alexe, Gabriela;Tolliday, Nicola;Inguilizian, Haig;Galinsky, Ilene;Stone, Richard M.;DeAngelo, Daniel J.;Roti, Giovanni;Aster, Jon C.;Hahn, William C.;Kung, Andrew L.;Stegmaier, Kimberly

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3α (GSK-3α) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3α induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and ...

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

Cet article passe en revue les travaux récents sur le rôle des micro-ARNs dans l'oncogenèse

The microcosmos of cancer
• Nature, Vol. 482 (7385), pp. 347-355, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle des micro-ARNs dans l'oncogenèse

“The microcosmos of cancer”

• Lujambio, Amaia;Lowe, Scott W.

The discovery of microRNAs (miRNAs) almost two decades ago established a new paradigm of gene regulation. During the past ten years these tiny non-coding RNAs have been linked to virtually all known physiological and pathological processes, including cancer. In the same way as certain key protein-coding genes, miRNAs can be deregulated in cancer, in which they can function as a group to mark differentiation states or individually as bona fide oncogenes or tumour suppressors. Importantly, miRNA biology can be harnessed experimentally to investigate cancer phenotypes or used therapeutically as a target for drugs or as the drug itself.

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

Progression et métastases

Menée in vitro et à l'aide de xénogreffes, cette étude montre le rôle joué par une protéine des cellules tumorales, ANGPTL2, dans le processus métastatique

Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis
• Cancer Research, sous presse, 2012 (résumé)

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Menée in vitro et à l'aide de xénogreffes, cette étude montre le rôle joué par une protéine des cellules tumorales, ANGPTL2, dans le processus métastatique

“Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis”

• Endo, Motoyoshi;Nakano, Masahiro;Kadomatsu, Tsuyoshi;Fukuhara, Shigetomo;Kuroda, Hiroaki;Mikami, Shuji;Hato, Tai;Aoi, Jun;Horiguchi, Haruki;Miyata, Keishi;Odagiri, Haruki;Masuda, Tetsuro;Harada, Masahiko;Horio, Hirotoshi;Hishima, Tsunekazu;Nomori, Hiroaki;Ito, Takaaki;Yamamoto, Yutaka;Minami, Takashi;Okada, Seiji;Takahashi, Takashi;Mochizuki, Naoki;Iwase, Hirotaka;Oike, Yuichi

Strategies to inhibit metastasis have been mainly unsuccessful in part due to insufficient mechanistic understanding. Here we report evidence of critical role for the angiopoietin-like protein ANGPTL2 in metastatic progression. In mice, Angptl2 has been implicated in inflammatory carcinogenesis but it has not been studied in human tumors. In lung cancer patients, elevated levels of ANGPTL2 expression in tumor cells within the primary tumor were associated with a reduction in the period of disease-free survival after surgical resection. Transcription factors NFATc, ATF2 and c-Jun upregulated in aggressive tumor cells promoted increased Angptl2 expression. Most notably, tumor-cell derived ANGPTL2 increased in vitro motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. In xenograft mouse models, tumor-cell derived ANGPTL2 accelerated metastasis and shortened survival, whereas attenuating ANGPTL2 expression in tumor cells blunted ...

Mots clés : Poumon; Biologie (Progression et métastases)

A partir de données cliniques portant sur 619 patientes atteintes d'un cancer épithélial de l'ovaire et à l'aide d'échantillons tumoraux et de modèles murins, cette étude analyse les mécanismes associés à une thrombocytose paranéoplasique

Paraneoplastic Thrombocytosis in Ovarian Cancer
• New England Journal of Medicine, Vol. 366 (7), pp. 610-618, 2012 (résumé)

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A partir de données cliniques portant sur 619 patientes atteintes d'un cancer épithélial de l'ovaire et à l'aide d'échantillons tumoraux et de modèles murins, cette étude analyse les mécanismes associés à une thrombocytose paranéoplasique

“Paraneoplastic Thrombocytosis in Ovarian Cancer”

• Stone, Rebecca L.;Nick, Alpa M.;McNeish, Iain A.;Balkwill, Frances;Han, Hee Dong;Bottsford-Miller, Justin;Rupaimoole, Rajesha;Armaiz-Pena, Guillermo N.;Pecot, Chad V.;Coward, Jermaine;Deavers, Michael T.;Vasquez, Hernan G.;Urbauer, Diana;Landen, Charles N.;Hu, Wei;Gershenson, Hannah;Matsuo, Koji;Shahzad, Mian M.K.;King, Erin R.;Tekedereli, Ibrahim;Ozpolat, Bulent;Ahn, Edward H.;Bond, Virginia K.;Wang, Rui;Drew, Angela F.;Gushiken, Francisca;Collins, Katherine;DeGeest, Koen;Lutgendorf, Susan K.;Chiu, Wah;Lopez-Berestein, Gabriel;Afshar-Kharghan, Vahid;Sood, Anil K.

Background : The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear. Methods : We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained. Results : Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also ...

Mots clés : Ovaire; Biologie (Progression et métastases)

Menée in vitro, cette étude met en évidence le rôle joué par la cystine, produite par des cellules de l'environnement stromal, dans la survie de cellules leucémiques soumises à l'agression de molécules cytotoxiques

Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia
• Nature Cell Biology, sous presse, 2012 (résumé)

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Menée in vitro, cette étude met en évidence le rôle joué par la cystine, produite par des cellules de l'environnement stromal, dans la survie de cellules leucémiques soumises à l'agression de molécules cytotoxiques

“Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia”

• Zhang, Wan;Trachootham, Dunyaporn;Liu, Jinyun;Chen, Gang;Pelicano, Helene;Garcia-Prieto, Celia;Lu, Weiqin;Burger, Jan A.;Croce, Carlo M.;Plunkett, William;Keating, Michael J.;Huang, Peng

Tissue stromal cells interact with leukaemia cells and profoundly affect their viability and drug sensitivity. Here we show a biochemical mechanism by which bone marrow stromal cells modulate the redox status of chronic lymphocytic leukaemia (CLL) cells and promote cellular survival and drug resistance. Primary CLL cells from patients exhibit a limited ability to transport cystine for glutathione (GSH) synthesis owing to a low expression level of Xc-transporter. In contrast, bone marrow stromal cells effectively import cystine and convert it to cysteine, which is then released into the microenvironment for uptake by CLL cells to promote GSH synthesis. The elevated level of GSH enhances leukaemia cell survival and protects them from drug-induced cytotoxicity. Furthermore, disabling this protective mechanism significantly sensitizes CLL cells to drug treatment in the stromal environment. This stromal–leukaemia interaction is critical for CLL cell survival and represents a key ...
Good neighbours in the tumour stroma reduce oxidative stress
• Nature Cell Biology, sous presse, 2012 (commentaire)

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Menée in vitro, cette étude met en évidence le rôle joué par la cystine, produite par des cellules de l'environnement stromal, dans la survie de cellules leucémiques soumises à l'agression de molécules cytotoxiques

“Good neighbours in the tumour stroma reduce oxidative stress”

• DeBerardinis, Ralph J.

Tumour cells undergo oncogene-regulated metabolic reprogramming that maximizes survival and growth. However, little is known about metabolic interactions between tumour cells and their non-malignant neighbours in the stroma. Bone-marrow-derived stromal cells are now shown to provide cysteine, an essential nutrient that enables leukaemia cells to resist oxidative stress.

Mots clés : Leucémie; Biologie (Progression et métastases)

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel le facteur de croissance VEGF-D favorise le processus métastatique

VEGF-D Promotes Tumor Metastasis by Regulating Prostaglandins Produced by the Collecting Lymphatic Endothelium
• Cancer cell, Vol. 21 (2), pp. 181-195, 2012 (résumé)

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Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel le facteur de croissance VEGF-D favorise le processus métastatique

“VEGF-D Promotes Tumor Metastasis by Regulating Prostaglandins Produced by the Collecting Lymphatic Endothelium”

• Karnezis, Tara;Shayan, Ramin;Caesar, Carol;Roufail, Sally;Harris, Nicole C;Ardipradja, Kathryn;Zhang, You Fang;Williams, Steven P;Farnsworth, Rae H;Chai, Ming G;Rupasinghe, Thusitha W T.;Tull, Dedreia L;Baldwin, Megan E;Sloan, Erica K;Fox, Stephen B;Achen, Marc G;Stacker, Steven A

Lymphatic metastasis is facilitated by lymphangiogenic growth factors VEGF-C and VEGF-D that are secreted by some primary tumors. We identified regulation of PGDH, the key enzyme in prostaglandin catabolism, in endothelial cells of collecting lymphatics, as a key molecular change during VEGF-D-driven tumor spread. The VEGF-D-dependent regulation of the prostaglandin pathway was supported by the finding that collecting lymphatic vessel dilation and subsequent metastasis were affected by nonsteroidal anti-inflammatory drugs (NSAIDs), known inhibitors of prostaglandin synthesis. Our data suggest a control point for cancer metastasis within the collecting lymphatic endothelium, which links VEGF-D/VEGFR-2/VEGFR-3 and the prostaglandin pathways. Collecting lymphatics therefore play an active and important role in metastasis and may provide a therapeutic target to restrict tumor spread. º Collecting lymphatics undergo critical morphological changes during metastasis º Isolated and ...
VEGF-D(ilated) Lymphatics as Gateways to Metastasis
• Cancer cell, Vol. 21 (2), pp. 139-140, 2012 (commentaire)

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Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel le facteur de croissance VEGF-D favorise le processus métastatique

“VEGF-D(ilated) Lymphatics as Gateways to Metastasis”

• Rak, Janusz

VEGF-C and VEGF-D have been implicated in lymphatic metastasis, mainly as inducers of new intra/peritumoral capillary lymphatics. In this issue of Cancer Cell, Karnezis and colleagues challenge this notion and demonstrate that tumor-derived VEGF-D promotes metastasis by causing prostaglandin-dependent dilation of collecting lymphatics outside of the tumor mass.

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

Cet article passe en revue les travaux récents sur le rôle des modifications de l'environnement de l'enveloppe nucléaire dans le développement et la progression d'une tumeur

The nuclear envelope environment and its cancer connections
• Nature Reviews Cancer, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle des modifications de l'environnement de l'enveloppe nucléaire dans le développement et la progression d'une tumeur

“The nuclear envelope environment and its cancer connections”

• Chow, Kin-Hoe;Factor, Rachel E.;Ullman, Katharine S.

Because of the association between aberrant nuclear structure and tumour grade, nuclear morphology is an indispensible criterion in the current pathological assessment of cancer. Components of the nuclear envelope environment have central roles in many aspects of cell function that affect tumour development and progression. As the roles of the nuclear envelope components, including nuclear pore complexes and nuclear lamina, are being deciphered in molecular detail there are opportunities to harness this knowledge for cancer therapeutics and biomarker development. In this Review, we summarize the progress that has been made in our understanding of the nuclear envelope and the implications of changes in this environment for cancer biology.

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

Ressources et infrastructures (Biologie)

Ces deux études décrivent un modèle murin de glioblastome surexprimant le gène Myc

An Animal Model of MYC-Driven Medulloblastoma
• Cancer cell, Vol. 21 (2), pp. 155-167, 2012 (article en libre accès)

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Ces deux études décrivent un modèle murin de glioblastome surexprimant le gène Myc

“An Animal Model of MYC-Driven Medulloblastoma”

• Pei, Yanxin;Moore, Colin E;Wang, Jun;Tewari, Alok K;Eroshkin, Alexey;Cho, Yoon-Jae;Witt, Hendrik;Korshunov, Andrey;Read, Tracy-Ann;Sun, Julia L;Schmitt, Earlene M;Miller, C. Ryan;Buckley, Anne F;McLendon, Roger E;Westbrook, Thomas F;Northcott, Paul A;Taylor, Michael D;Pfister, Stefan M;Febbo, Phillip G;Wechsler-Reya, Robert J

Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here, we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB and identify a novel model that can be used to test therapies for this devastating disease. º Myc promotes proliferation of cerebellar stem cells in vitro º Mutant p53 cooperates with Myc to transform stem cells into tumors º Tumors resulting from Myc and mutant p53 resemble human ...
A Mouse Model of the Most Aggressive Subgroup of Human Medulloblastoma
• Cancer cell, Vol. 21 (2), pp. 168-180, 2012 (article en libre accès)

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Ces deux études décrivent un modèle murin de glioblastome surexprimant le gène Myc

“A Mouse Model of the Most Aggressive Subgroup of Human Medulloblastoma”

• Kawauchi, Daisuke ; Robinson, Giles ; Uziel, Tamar ; Gibson, Paul ; Rehg, Jerold ; Gao, Cuilan ; Finkelstein, David ; Qu, Chunxu ; Pounds, Stanley ; Ellison, David W ; Gilbertson, Richard J ; Roussel, Martine F

Medulloblastomas that display a large cell/anaplastic morphology and overexpress the cellular c-MYC gene are highly aggressive and carry a very poor prognosis. This so-called MYC-subgroup differs in its histopathology, gene expression profile, and clinical behavior from other forms of medulloblastoma. We generated a mouse model of MYC-subgroup medulloblastoma by transducing Trp53-null cerebellar progenitor cells with Myc. The cardinal features of these mouse medulloblastomas closely mimic those of human MYC-subgroup tumors and significantly differ from mouse models of the Sonic-Hedgehog- and WNT-disease subgroups. This mouse model should significantly accelerate understanding and treatment of the most aggressive form of medulloblastoma and infers distinct roles for MYC and MYCN in tumorigenesis. º Myc overexpression and Trp53 loss induce large cell anaplastic medulloblastoma º The transcriptomes of human and mouse MYC-subgroup medulloblastoma are similar º MYC-subgroup ...
Three Down and One To Go: Modeling Medulloblastoma Subgroups
• Cancer cell, Vol. 21 (2), pp. 137-138, 2012 (commentaire)

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Ces deux études décrivent un modèle murin de glioblastome surexprimant le gène Myc

“Three Down and One To Go: Modeling Medulloblastoma Subgroups”

• Eberhart, Charles G

In this issue of Cancer Cell, Pei et al. and Kawauchi et al. describe murine models of an aggressive medulloblastoma subtype driven by Myc. These tumors have a cellular origin, microscopic appearance, and molecular profile distinct from those of three other major subgroups. Thus, the models fill a significant clinical need.

Mots clés : Système nerveux central; Biologie (Ressources et infrastructures (Biologie))

Cet article passe en revue les travaux récents sur la biologie des cancers du sein

Progress in breast cancer research
• Proceedings of the National Academy of Sciences, sous presse, 2012 (éditorial en libre accès)

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Cet article passe en revue les travaux récents sur la biologie des cancers du sein

“Progress in breast cancer research”

• Polyak, Kornelia;Vogt, Peter K.