A partir de données de séquençage du génome entier portant sur 140 patients atteints de cancer, cette étude dresse un catalogue des variations structurales somatiques et analyse les différences entre les mécanismes associés aux altérations somatiques et aux altérations de la lignée germinale

Diverse Mechanisms of Somatic Structural Variations in Human Cancer Genomes

Yang, Lixing ; Luquette, Lovelace J ; Gehlenborg, Nils ; Xi, Ruibin ; Haseley, Psalm S ; Hsieh, Chih-Heng ; Zhang, Chengsheng ; Ren, Xiaojia ; Protopopov, Alexei ; Chin, Lynda ; Kucherlapati, Raju ; Lee, Charles ; Park, Peter J

Identification of somatic rearrangements in cancer genomes has accelerated through analysis of high-throughput sequencing data. However, characterization of complex structural alterations and their underlying mechanisms remains inadequate. Here, applying an algorithm to predict structural variations from short reads, we report a comprehensive catalog of somatic structural variations and the mechanisms generating them, using high-coverage whole-genome sequencing data from 140 patients across ten [...]

Cet article passe en revue les travaux récents sur le rôle de mutations des gènes associés aux protéines G et aux récepteurs couplés aux protéines G dans les processus de tumorigenèse

The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer

O'Hayre, Morgan ; Vazquez-Prado, Jose ; Kufareva, Irina ; Stawiski, Eric W. ; Handel, Tracy M. ; Seshagiri, Somasekar ; Gutkind, J. Silvio

Aberrant expression and activity of G proteins and G-protein-coupled receptors (GPCRs) are frequently associated with tumorigenesis. Deep sequencing studies show that 4.2% of tumours carry activating mutations in GNAS (encoding G

Cet article passe en revue les travaux récents sur le paysage génomique des leucémies lymphocytaires chroniques

The genomic landscape of chronic lymphocytic leukemia: clinical implications

Quesada, Victor ; Ramsay, Andrew ; Rodriguez, David ; Puente, Xose ; Campo, Elias ; López-Otín, Carlos

A precise understanding of the genomic and epigenomic features of chronic lymphocytic leukemia (CLL) may benefit the study of the disease's staging and treatment. While recent reports have shed some light on these aspects, several challenges need to be addressed before translating this research into clinical practice. Thus, even the best candidate driver genes display low mutational rates compared to other tumors. This means that a large percentage of cases do not display clear tumor-driving [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le facteur de transcription Brn3a, normalement impliqué dans le développement neuronal, favorise la prolifération des cellules de mélanome

The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival

Hohenauer, Tobias ; Berking, Carola ; Schmidt, Andreas ; Haferkamp, Sebastian ; Senft, Daniela ; Kammerbauer, Claudia ; Fraschka, Sabine ; Graf, Saskia Anna ; Irmler, Martin ; Beckers, Johannes ; Flaig, Michael ; Aigner, Achim ; Höbel, Sabrina ; Hoffmann, Franziska ; Hermeking, Heiko ; Rothenfusser, Simon ; Endres, Stefan ; Ruzicka, Thomas ; Besch, Robert

Pigment cells and neuronal cells both are derived from the neural crest. Here, we describe the Pit-Oct-Unc (POU) domain transcription factor Brn3a, normally involved in neuronal development, to be frequently expressed in melanoma, but not in melanocytes and nevi. RNAi-mediated silencing of Brn3a strongly reduced the viability of melanoma cell lines and decreased tumour growth in vivo. In melanoma cell lines, inhibition of Brn3a caused DNA double-strand breaks as evidenced by [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, après la perte du gène APC, le gène RAC1, en activant notamment la signalisation

ROS Production and NF-

Myant, Kevin B ; Cammareri, Patrizia ; McGhee, Ewan J ; Ridgway, Rachel A ; Huels, David J ; Cordero, Julia B ; Schwitalla, Sarah ; Kalna, Gabriela ; Ogg, Erinn-Lee ; Athineos, Dimitris ; Timpson, Paul ; Vidal, Marcos ; Murray, Graeme I ; Greten, Florian R ; Anderson, Kurt I ; Sansom, Owen J

The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor [...]

Menée sur des échantillons tumoraux prélevés sur 1 302 patientes atteintes d'un cancer du sein, cette étude analyse les profils d'expression des micro-ARNs et met en évidence leur rôle modulateur dans les cancers du sein ne présentant pas d'anomalies du nombre de copies de gènes

The shaping and functional consequences of the microRNA landscape in breast cancer

Dvinge, Heidi ; Git, Anna ; Graf, Stefan ; Salmon-Divon, Mali ; Curtis, Christina ; Sottoriva, Andrea ; Zhao, Yongjun ; Hirst, Martin ; Armisen, Javier ; Miska, Eric A. ; Chin, Suet-Feung ; Provenzano, Elena ; Turashvili, Gulisa ; Green, Andrew ; Ellis, Ian ; Aparicio, Sam ; Caldas, Carlos

MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1,302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and [...]

Menée à l'aide de modèles murins de cancer du sein, cette étude met en évidence des mécanismes par lesquels le gène Palb2 joue un rôle de suppresseur de tumeurs

Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer

Bowman-Colin, Christian ; Xia, Bing ; Bunting, Samuel ; Klijn, Christiaan ; Drost, Rinske ; Bouwman, Peter ; Fineman, Laura ; Chen, Xixi ; Culhane, Aedin C. ; Cai, Hong ; Rodig, Scott J. ; Bronson, Roderick T. ; Jonkers, Jos ; Nussenzweig, André ; Kanellopoulou, Chryssa ; Livingston, David M.

Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2-mediated DNA repair and tumor suppression functions, we targeted Palb2 in the mouse. Palb2-deficient murine ES cells [...]

Menée in vitro et in vivo, cette étude met en évidence deux sous-types de cellules souches de gliomes en corrélation avec deux sous-types cliniques de gliomes de haut grade et, en particulier, identifie le rôle joué par la signalisation ALDH1A3 dans les cellules souches mésenchymateuses

Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3

Mao, Ping ; Joshi, Kaushal ; Li, Jianfeng ; Kim, Sung-Hak ; Li, Peipei ; Santana-Santos, Lucas ; Luthra, Soumya ; Chandran, Uma R. ; Benos, Panayiotis V. ; Smith, Luke ; Wang, Maode ; Hu, Bo ; Cheng, Shi-Yuan ; Sobol, Robert W. ; Nakano, Ichiro

Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du gène Ras et en stabilisant la protéine NF1, la protéine Cul3 joue un rôle de suppresseur de tumeurs dans les glioblastomes

Identifying the ubiquitin ligase complex that regulates the NF1 tumor suppressor and Ras

Hollstein, Pablo E ; Cichowski, Karen

The NF1 tumor suppressor protein, neurofibromin, is a negative regulator of Ras. Neurofibromin is dynamically regulated by the proteasome and its degradation and re-expression are essential for maintaining appropriate levels of Ras-GTP. Like p53, NF1/neurofibromin can be inactivated in cancer by both mutations and excessive proteasomal destruction; however, little is known about the mechanisms that underlie this latter process. Here we show that a Cullin 3 (Cul3)/KBTBD7 complex controls both [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par la signalisation TGFβ dans les cellules myéloïdes pour favoriser le processus métastatique

Transforming growth factor β signaling in myeloid cells is required for tumor metastasis

Pang, Yanli ; Gara, Sudheer Kumar ; Achyut, Bhagelu Ram ; Li, Zhaoyang ; Yan, Hannah H ; Day, Chi-Ping ; Weiss, Jonathan M ; Trinchieri, Giorgio ; Morris, John C ; Yang, Li

TGFβ is over expressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGFβ functions as both a tumor suppressor and a tumor promoter. Here we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2MyeKO) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2MyeKO bone marrow recapitulates the inhibited metastasis phenotype. This effect is mediated through decreased production of [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels l'intégrine α4β1, activée par la signalisation PI3Kα, favorise la formation d'une niche métastatique dans les ganglions lymphatiques

PI3Kα activates integrin α4β1 to establish a metastatic niche in lymph nodes

Garmy-Susini, Barbara ; Avraamides, Christie J. ; Desgrosellier, Jay S. ; Schmid, Michael C. ; Foubert, Philippe ; Ellies, Lesley G. ; Lowy, Andrew M. ; Blair, Sarah L. ; Vandenberg, Scott R. ; Datnow, Brian ; Wang, Huan-You ; Cheresh, David A. ; Varner, Judith

Lymph nodes are initial sites of tumor metastasis, yet whether the lymph node microenvironment actively promotes tumor metastasis remains unknown. We show here that VEGF-C/PI3Kα-driven remodeling of lymph nodes promotes tumor metastasis by activating integrin α4β1 on lymph node lymphatic endothelium. Activated integrin α4β1 promotes expansion of the lymphatic endothelium in lymph nodes and serves as an adhesive ligand that captures vascular cell adhesion molecule 1 (VCAM-1)+ metastatic tumor [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels le co-activateur transcriptionnel SRC-3 favorise le développement d'un cancer de la prostate résistant à la castration

The Steroid Receptor Coactivator-3 Is Required for the Development of Castration-resistant Prostate Cancer

Tien, Jean Ching-Yi ; Liu, Zhaoliang ; Liao, Lan ; Wang, Fen ; Xu, Yixiang ; Wu, Ye-lin ; Zhou, Niya ; Ittmann, Michael M ; Xu, Jianming

The transcriptional coactivator SRC-3 plays a key role to enhance prostate cancer (CaP) cell proliferation. Although SRC-3 is highly expressed in advanced CaP, its role in castration resistant CaP (CRPC) driven by PTEN mutation is unknown. We documented elevated SRC-3 in human CRPC and in PTEN-negative human CaP. Patients with high SRC-3 and undetectable PTEN exhibited decreased recurrence-free survival. To explore the causal relationship in these observations, we generated mice in which both [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en stabilisant la protéine SNAIL1, le récepteur DDR2 du collagène de type I favorise le processus métastatique d'un cancer du sein

The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis

Zhang, Kun ; Corsa, Callie A. ; Ponik, Suzanne M. ; Prior, Julie L. ; Piwnica-Worms, David ; Eliceiri, Kevin W. ; Keely, Patricia J. ; Longmore, Gregory D.

Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in [...]

Cet article passe en revue les travaux récents sur le rôle des longs ARNs non codants dans les différentes phases du développement d'un cancer

Long noncoding RNAs and the genetics of cancer

Cheetham, S. W. ; Gruhl, F. ; Mattick, J. S. ; Dinger, M. E.

Cancer is a disease of aberrant gene expression. While the genetic causes of cancer have been intensively studied, it is becoming evident that a large proportion of cancer susceptibility cannot be attributed to variation in protein-coding sequences. This is highlighted by genome-wide association studies in cancer that reveal that more than 80% of cancer-associated SNPs occur in noncoding regions of the genome. In this review, we posit that a significant fraction of the genetic aetiology of [...]