Menée à partir de 12 échantillons tumoraux prélevés sur des patients atteints d'un cancer lié au papillomavirus humain (HPV), cette étude de séquençage du génome entier met en évidences des mécanismes par lesquels l'intégration du génome du HPV favorise l'instabilité du génome de l'hôte

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

Akagi, Keiko ; Li, Jingfeng ; Broutian, Tatevik R ; Padilla-Nash, Hesed ; Xiao, Weihong ; Jiang, Bo ; Rocco, James W ; Teknos, Theodoros N ; Kumar, Bhavna ; Wangsa, Danny ; He, Dandan ; Ried, Thomas ; Symer, David E ; Gillison, Maura L

Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions and chromosomal translocations. We present a model of 'looping' by which HPV [...]

Menée initialement sur 10 échantillons prélevés sur des patients atteints d'une leucémie à tricholeucocytes exprimant le gène IGHV4-34, puis validée sur 21 échantillons complémentaires, cette étude identifie la présence fréquente de mutations activatrices du gène MAP2K1

High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias

Waterfall, Joshua J. ; Arons, Evgeny ; Walker, Robert L. ; Pineda, Marbin ; Roth, Laura ; Killian, J. Keith ; Abaan, Ogan D. ; Davis, Sean R. ; Kreitman, Robert J. ; Meltzer, Paul S.

To understand the genetic mechanisms driving variant and IGHV4-34–expressing hairy-cell leukemias, we performed whole-exome sequencing of leukemia samples from ten affected individuals, including six with matched normal samples. We identified activating mutations in the MAP2K1 gene (encoding MEK1) in 5 of these 10 samples and in 10 of 21 samples in a validation set (overall frequency of 15/31), suggesting potential new strategies for treating individuals with these diseases.

Menée à partir de 194 échantillons tumoraux et 209 échantillons sanguins prélevés sur 403 patients non apparentés atteints d'un rétinoblastome, cette étude analyse le spectre des modifications génétiques et épigénétiques du gène RB1

Spectrum of RB1 mutations identified in 403 retinoblastoma patients

Price, Elizabeth A ; Price, Kelly ; Kolkiewicz, Kelly ; Hack, Simon ; Reddy, M Ashwin ; Hungerford, John L ; Kingston, Judith E ; Onadim, Zerrin

Background Retinoblastoma (RB) is a malignant, childhood tumour of the developing retina that occurs with an estimated frequency of 1 in 20 000. Identification of oncogenic mutations in the RB1 gene aids in the clinical management of families with a heritable predisposition to RB. Here we present the spectrum of genetic and epigenetic changes identified in 194 tumours and 209 blood samples, from 403 unrelated RB patients. Methods Mutation screening was carried out across all 27 RB1 exons and [...]

Menée à partir d'échantillons tumoraux prélevés sur 3 patientes atteintes d'un cancer de l'épithélium ovarien de stade IIIC/IV, cette étude analyse l'hétérogénéité intra-tumorale du point de vue des différences régionales dans les altérations génomiques et l'expression de certains gènes

Genomic and transcriptomic plasticity in treatment-naïve ovarian cancer

Hoogstraat, Marlous ; de Pagter, Mirjam S ; Cirkel, Geert A ; van Roosmalen, Markus J ; Harkins, Timothy T ; Duran, Karen ; Kreeftmeijer, Jennifer ; Renkens, Ivo ; Witteveen, Petronella O ; Lee, Clarence C ; Nijman, Isaac J ; Guy, Tanisha ; van 't Slot, Ruben ; Jonges, Trudy N ; Lolkema, Martijn P ; Koudijs, Marco J ; Zweemer, Ronald P ; Voest, Emile E ; Cuppen, Edwin ; Kloosterman, Wigard P

Intra-tumor heterogeneity is a hallmark of many cancers and may lead to therapy resistance or interfere with personalized treatment strategies. Here, we combined topographic mapping of somatic breakpoints and transcriptional profiling to probe intra-tumor heterogeneity of treatment-naïve stage IIIC/IV epithelial ovarian cancer. We observed that most substantial differences in genomic rearrangement landscapes occurred between metastases in the omentum and peritoneum versus tumor sites in the [...]

Menée dans le cadre du projet "The Cancer Genome Atlas" à partir de 277 échantillons tumoraux prélevés sur des patients atteints d'un cancer du côlon-rectum ou de l'endomètre, cette étude analyse la prévalence et les conséquences fonctionnelles d'une instabilité des microsatellites

The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer Genomes

Kim, Tae-Min ; Laird, Peter W ; Park, Peter J

Microsatellites simple tandem repeats present at millions of sites in the human genome can shorten or lengthen due to a defect in DNA mismatch repair. We present here a comprehensive genome-wide analysis of the prevalence, mutational spectrum, and functional consequences of microsatellite instability (MSI) in cancer genomes. We analyzed MSI in 277 colorectal and endometrial cancer genomes (including 57 microsatellite-unstable ones) using exome and whole-genome sequencing data. Recurrent MSI [...]

Cet article passe en revue les travaux récents sur le rôle de l'adénosine et de ses récepteurs dans la régulation des interactions entre les cellules immunitaires, inflammatoires, endothéliales et cancéreuses

Immunity, inflammation and cancer: a leading role for adenosine

Antonioli, Luca ; Blandizzi, Corrado ; Pacher, Pal ; Hasko, Gyorgy

Cancer is a complex disease that is dictated by both cancer cell-intrinsic and cell-extrinsic processes. Adenosine is an ancient extracellular signalling molecule that can regulate almost all aspects of tissue function. As such, several studies have recently highlighted a crucial role for adenosine signalling in regulating the various aspects of cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses the role of adenosine and its receptors in [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes de coopération entre les signalisations BRAFV600E et PI3K dans le développement d'un mélanome

Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma

Marsh Durban, Victoria ; Deuker, Marian M. ; Bosenberg, Marcus W. ; Phillips, Wayne ; McMahon, Martin

Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase–dependent and –independent tumor suppressor activities, we [...]

Menée sur 57 échantillons tumoraux et in vitro, cette étude française met en évidence le rôle joué par la signalisation Wnt dans la tumorigenèse d'une neurofibromatose de type 1

The activation of the WNT signalling pathway is a hallmark in Neurofibromatosis type 1 tumorigenesis

Luscan, Armelle ; Shackleford, Ghjuvan'Ghjacumu ; Masliah-Planchon, Julien ; Laurendeau, Ingrid ; Ortonne, Nicolas ; Varin, Jennifer ; Lallemand, Francois ; Leroy, Karen ; Dumaine, Valerie ; Hivelin, Mikael ; Borderie, Didier ; De Raedt, Thomas ; Valeyrie-Allanore, Laurence ; Larousserie, Frederique ; Terris, Benoit ; Lantieri, Laurent ; Vidaud, Michel ; Vidaud, Dominique ; Wolkenstein, Pierre ; Parfait, Beatrice ; Bièche, Ivan ; Massaad, Charbel ; Pasmant, Eric

Purpose: The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNSTs) that are resistant to therapies. Experimental design: The aim of this study was to identify an additional pathway in the NF1-tumorigenesis. We focused our work on Wnt signalling that is highly implicated in cancer, mainly in regulating the proliferation of cancer [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la plectine, normalement une protéine de structure intracellulaire, favorise le développement d'un adénocarcinome canalaire du pancréas lorsqu'elle est présente sur la surface extracellulaire des cellules cancéreuses

Unexpected gain of function for the scaffolding protein plectin due to mislocalization in pancreatic cancer

Shin, Soo J. ; Smith, Jeffrey A. ; Rezniczek, Günther A. ; Pan, Sheng ; Chen, Ru ; Brentnall, Teresa A. ; Wiche, Gerhard ; Kelly, Kimberly A.

We recently demonstrated that plectin is a robust biomarker for pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive malignancies. In normal physiology, plectin is an intracellular scaffolding protein, but we have demonstrated localization on the extracellular surface of PDAC cells. In this study, we confirmed cell surface localization. Interestingly, we found that plectin cell surface localization was attributable to its presence in exosomes secreted from PDAC cells, which is [...]

Menée à l'aide d'un modèle murin, cette étude montre que l'inactivation du gène RUNX3 est un événement précoce et crucial dans le développement d'un adénocarcinome du poumon

Runx3 Inactivation Is a Crucial Early Event in the Development of Lung Adenocarcinoma

Lee, You-Soub ; Lee, Jung-Won ; Jang, Ju-Won ; Chi, Xin-Zi ; Kim, Jang-Hyun ; Li, Ying-Hui ; Kim, Min-Kyu ; Kim, Da-Mi ; Choi, Byeung-Sub ; Kim, Eung-Gook ; Chung, Jin-Haeng ; Lee, Ok-Jun ; Lee, You-Mie ; Suh, Joo-Won ; Chuang, Linda Shyue Huey ; Ito, Yoshiaki ; Bae, Suk-Chul

Targeted inactivation of Runx3 in mouse lung induced mucinous and nonmucinous adenomas and markedly shortened latency of adenocarcinoma formation induced by oncogenic K-Ras. RUNX3 was frequently inactivated in K-RAS mutated human lung adenocarcinomas. A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of [...]

Menée à l'aide d'un modèle murin de cancer du sein, cette étude met en évidence des mécanismes par lesquels le gène MKK3 joue un rôle de suppresseur de tumeurs

MAPK kinase 3 is a tumor suppressor with reduced copy number in breast cancer

MacNeil, Adam J ; Jiao, Shun-Chang ; McEachern, Lori A ; Yang, Yong Jun ; Dennis, Amanda ; Yu, Haiming ; Xu, Zhaolin ; Marshall, Jean S. ; Lin, Tong-Jun

Cancers are initiated as a result of changes that occur in the genome. Identification of gains and losses in the structure and expression of tumor suppressor genes and oncogenes lies at the root of the understanding of cancer cell biology. Here we show that the MAPK kinase MKK3 suppresses the growth of breast cancer where it varies in copy number. A pervasive loss of MKK3 gene copy number in breast cancer patients is associated with an impairment of MKK3 expression and protein level in [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le micro-ARN miR-192 inhibe la formation de métastases hépatiques d'un cancer du côlon

MicroRNA-192 suppresses liver metastasis of colon cancer

Geng, L. ; Chaudhuri, A. ; Talmon, G. ; Wisecarver, J. L. ; Are, C. ; Brattain, M. ; Wang, J.

Metastasis causes most deaths from colon cancer yet mechanistic understanding and therapeutic options remain limited. Here we show that expression of microRNA (miR)-192 is inversely correlated with metastatic potential of colon cancer cells. Ectopic expression of miR-192 sensitizes colon cancer cells to growth factor deprivation stress-induced apoptosis, whereas inhibition of miR-192 confers resistance. Overexpression of miR-192 inhibits metastatic colonization to the liver in an orthotopic [...]

Cet article passe en revue les perspectives offertes par l'étude du développement embryonnaire pour mieux comprendre les mécanismes de progression tumorale

Epithelial Plasticity: A Common Theme in Embryonic and Cancer Cells

Nieto, M. Angela

During embryonic development, many cells are born far from their final destination and must travel long distances. To become motile and invasive, embryonic epithelial cells undergo a process of mesenchymal conversion known as epithelial-to-mesenchymal transition (EMT). Likewise, EMT can be seen in cancer cells as they leave the primary tumor and disseminate to other parts of the body to colonize distant organs and form metastases. In addition, through the reverse process [...]

Cet article passe en revue les travaux récents sur les mécanismes associés à la dormance des cellules métastatiques et à leur réactivation

Mechanisms Governing Metastatic Dormancy and Reactivation

Giancotti, Filippo G

Many cancer patients suffer from metastatic relapse several years after they have undergone radical surgery. Early cancer cell dissemination followed by a protracted period of dormancy potentially explains this prevalent clinical behavior. Increasing evidence suggests that the metastasis-initiating cells are cancer stem cells or revert to this functional state upon infiltrating a target organ. Their entry into dormancy and subsequent reactivation are governed by intrinsic programs and by [...]

Menée à l'aide d'un modèle numérique et in vitro, cette étude met en évidence des mécanismes par lesquels des modifications du métabolisme de cellules cancéreuses, liées à l'effet Warburg, induisent un microenvironnement favorisant les cellules tumorales au détriment des autres cellules

Emergence of spatial structure in the tumor microenvironment due to the Warburg effect

Carmona-Fontaine, Carlos ; Bucci, Vanni ; Akkari, Leila ; Deforet, Maxime ; Joyce, Johanna A. ; Xavier, Joao B.

Drastic metabolic alterations, such as the Warburg effect, are found in most if not all types of malignant tumors. Emerging evidence shows that cancer cells benefit from these alterations, but little is known about how they affect noncancerous stromal cells within the tumor microenvironment. Here we show that cancer cells are better adapted to metabolic changes in the microenvironment, leading to the emergence of spatial structure. A clear example of tumor spatial structure is the localization [...]

Cet article passe en revue les perspectives offertes par les concepts de "compromis évolutifs dans l'allocation des ressources entre différents traits d'histoire de vie" pour analyser la diversité phénotypique des cellules tumorales

Life history trade-offs in cancer evolution

Aktipis, C. Athena ; Boddy, Amy M. ; Gatenby, Robert A. ; Brown, Joel S. ; Maley, Carlo C.

Somatic evolution during cancer progression and therapy results in tumour cells that show a wide range of phenotypes, which include rapid proliferation and quiescence. Evolutionary life history theory may help us to understand the diversity of these phenotypes. Fast life history organisms reproduce rapidly, whereas those with slow life histories show less fecundity and invest more resources in survival. Life history theory also provides an evolutionary framework for phenotypic plasticity, which [...]

Menée à l'aide de biopuces mesurant l'expression de gènes dans 27 modèles murins génétiquement modifiés de cancer du sein, cette étude identifie des modèles reproduisant les principales caractéristiques de certains sous-types de cancer du sein dans l'espèce humaine

Transcriptomic classification of genetically engineered mouse models of breast cancer identifies human subtype counterparts

Pfefferle, Adam ; Herschkowitz, Jason ; Usary, Jerry ; Harrell, Joshua ; Spike, Benjamin ; Adams, Jessica ; Torres-Arzayus, Maria ; Brown, Myles ; Egan, Sean ; Wahl, Geoff ; Rosen, Jeffrey ; Perou, Charles

BACKGROUND:Human breast cancer is a heterogeneous disease consisting of multiple molecular subtypes. Genetically engineered mouse models are a useful resource for studying mammary cancers in vivo under genetically controlled and immune competent conditions. Identifying murine models with conserved human tumor features will facilitate etiology determinations, highlight the effects of mutations on pathway activation, and should improve preclinical drug testing. RESULTS:Transcriptomic profiles of [...]