A partir d'échantillons tumoraux prélevés pendant une période de 5 ans sur un patient atteint d'un myélome multiple, cette étude de séquençage du génome entier met en évidence l'évolution des variants génomiques depuis le diagnostic jusqu'à la progression vers une leucémie secondaire

Whole genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution and clonal tides

Egan, Jan B. ; Shi, Chang-Xin ; Tembe, Waibhav ; Christoforides, Alexis ; Kurdoglu, Ahmet ; Sinari, Shripad ; Middha, Sumit ; Asmann, Yan ; Schmidt, Jessica ; Braggio, Esteban ; Keats, Jonathan J. ; Fonseca, Rafael ; Bergsagel, P. Leif ; Craig, David W. ; Carpten, John D. ; Stewart, A. Keith

The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole genome sequencing (WGS) on four purified tumor samples and patient germline DNA drawn over a five year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single nucleotide [...]

Menée sur un modèle murin, cette étude met en évidence un mécanisme de nature métabolique par lequel l'expression du gène Kras favorise la croissance d'un adénocarcinome canalaire du pancréas

Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism

Ying, Haoqiang ; Kimmelman, Alec C ; Lyssiotis, Costas A ; Hua, Sujun ; Chu, Gerald C ; Fletcher-Sananikone, Eliot ; Locasale, Jason W ; Son, Jaekyoung ; Zhang, Hailei ; Coloff, Jonathan L ; Yan, Haiyan ; Wang, Wei ; Chen, Shujuan ; Viale, Andrea ; Zheng, Hongwu ; Paik, Ji-hye ; Lim, Carol ; Guimaraes, Alexander R ; Martin, Eric S ; Chang, Jeffery ; Hezel, Aram F ; Perry, Samuel R ; Hu, Jian ; Gan, Boyi ; Xiao, Yonghong ; Asara, John M ; Weissleder, Ralph ; Wang, Y.  Alan ; Chin, Lynda ; Cantley, Lewis C ; DePinho, Ronald A

Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on KrasG12D expression. Transcriptome and metabolomic analyses indicate that KrasG12D serves a vital role in controlling [...]

Menée à l'aide d'un modèle murin, cette étude suggère qu'une enzyme, la déubiquitinase Usp9x, joue un rôle de suppresseur de tumeurs dans l'adénocarcinome canalaire du pancréas

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Perez-Mancera, Pedro A. ; Rust, Alistair G. ; van der Weyden, Louise ; Kristiansen, Glen ; Li, Allen ; Sarver, Aaron L. ; Silverstein, Kevin A. T. ; Grutzmann, Robert ; Aust, Daniela ; Rummele, Petra ; Knosel, Thomas ; Herd, Colin ; Stemple, Derek L. ; Kettleborough, Ross ; Brosnan, Jacqueline A. ; Li, Ang ; Morgan, Richard ; Knight, Spencer ; Yu, Jun ; Stegeman, Shane ; Collier, Lara S. ; ten Hoeve, Jelle J. ; de Ridder, Jeroen ; Klein, Alison P. ; Goggins, Michael ; Hruban, Ralph H. ; Chang, David K. ; Biankin, Andrew V. ; Grimmond, Sean M. ; Wessels, Lodewyk F. A. ; Wood, Stephen A. ; Iacobuzio-Donahue, Christine A. ; Pilarsky, Christian ; Largaespada, David A. ; Adams, David J. ; Tuveson, David A.

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic KrasG12D to accelerate tumorigenesis and promote [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le facteur de transcription GATA2 dans les cellules de cancer du poumon non à petites cellules présentant des mutations du gène RAS

The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer

Kumar, Madhu S ; Hancock, David C ; Molina-Arcas, Miriam ; Steckel, Michael ; East, Phillip ; Diefenbacher, Markus ; Armenteros-Monterroso, Elena ; Lassailly, François ; Matthews, Nik ; Nye, Emma ; Stamp, Gordon ; Behrens, Axel ; Downward, Julian

Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide; nearly half contain mutations in the receptor tyrosine kinase/RAS pathway. Here we show that RAS-pathway mutant NSCLC cells depend on the transcription factor GATA2. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected. Integrated gene expression and genome occupancy analyses revealed GATA2 regulation of the proteasome, and IL-1-signaling, [...]

Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation de la protéine PI3K dans l'intestin induit des néoplasies de stade avancé

Mice Expressing Activated PI3K Develop Advanced Colon Cancer

Leystra, Alyssa A ; Deming, Dustin A ; Zahm, Christopher D ; Farhoud, Mohammed ; Paul Olson, Terrah J ; Hadac, Jamie N ; Nettekoven, Laura A ; Albrecht, Dawn M ; Clipson, Linda ; Sullivan, Ruth ; Washington, Mary K ; Torrealba, Jose R ; Weichert, Jamey P ; Halberg, Richard B

Aberrations in the phosphatidylinositide-3-kinase (PI3K) signaling pathway play a key role in the pathogenesis of numerous cancers by altering cellular growth, metabolism, proliferation, and apoptosis (1). Mutations in the catalytic domain of PI3K that generate a dominantly active kinase are commonly found in human colorectal cancers and have been thought to drive tumor progression, but not initiation (2). However, the effects of constitutively activated PI3K upon the intestinal mucosa have not [...]

Cet article passe en revue les travaux récents sur le rôle joué par des facteurs de transcription associés à la transition épithélio-mésenchymateuse dans les cellules souches cancéreuses et le processus métastatique

Cancer Stem Cells and Epithelial-Mesenchymal Transition: concepts and molecular links

Scheel, Christina ; Weinberg, Robert A.

The Epithelial-Mesenchymal Transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by carcinoma cells. EMT programs are orchestrated by a set of pleiotropically acting transcription factors (TFs). The actions of these EMT-TFs enable the early steps of metastasis: local invasion and subsequent dissemination of carcinoma cells to distant sites. However, in most malignancies, the subsequent outgrowth of [...]

Cet article passe en revue les travaux récents sur les interactions entre les cellules souches cancéreuses et le micro-environnement tumoral

The Bed and the Bugs: Interactions between the Tumor Microenvironment and Cancer Stem Cells

Castaño, Zafira ; Fillmore, Christine M. ; Kim, Carla F. ; McAllister, Sandra S.

Tumors have been increasingly recognized as organs with a complexity that approaches, and may even exceed, that of healthy tissues. When viewed from this perspective, the biology of a tumor can be understood only by studying tumor cell heterogeneity and the microenvironment that is constructed during the course of tumorigenesis and malignant progression. Recent work has revealed the existence of cancer stem cells, the “bugs”, with the capacity for self-renewal and tumor propagation. In [...]

Cet article passe en revue les travaux récents sur le rôle des anomalies de fonctionnement des mitochondries dans les cellules tumorales

Mitochondrial remodeling in cancer metabolism and survival: Potential for new therapies

Barbosa, Inês A. ; Machado, Nuno G. ; Skildum, Andrew ; Scott, Patricia M. ; Oliveira, Paulo J.

Mitochondria are semi-autonomous organelles that play essential roles in cellular metabolism and programmed cell death pathways. Genomic, functional and structural mitochondrial alterations have been associated with cancer. Some of those alterations may provide a selective advantage to cells, allowing them to survive and grow under stresses created by oncogenesis. Due to the specific alterations that occur in cancer cell mitochondria, these organelles may provide promising targets for cancer [...]

Cet article passe en revue les travaux récents sur le processus métastatique dans le myélome multiple

Myeloma as a model for the process of metastasis: implications for therapy

Ghobrial, Irene M.

Multiple Myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous "omas" throughout the skeleton indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la métalloprotéase matricielle Mmp10 dans les cellules souches de cancer du poumon

Matrix Metalloproteinase-10 Is Required for Lung Cancer Stem Cell Maintenance, Tumor Initiation and Metastatic Potential

Justilien, Verline ; Regala, Roderick P. ; Tseng, I. Chu ; Walsh, Michael P. ; Batra, Jyotica ; Radisky, Evette S. ; Murray, Nicole R. ; Fields, Alan P.

Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. [...]

Menée sur des modèles murins, cette étude met en évidence le rôle joué par les récepteurs des androgènes du micro-environnement tumoral dans la progression d'un cancer de la prostate

Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation, and metastasis

Ricke, Emily A. ; Williams, Karin ; Lee, Yi-Fen ; Couto, Suzana ; Wang, Yuzhuo ; Hayward, Simon W. ; Cunha, Gerald R. ; Ricke, William A.

It has been postulated that prostatic carcinogenesis is androgen dependent and that androgens mediate their effects primarily through epithelial cells however, definitive proof of androgen hormone action in prostate cancer progression is lacking. Here we demonstrate through genetic loss of function experiments that prostate cancer (PRCA)-progression is androgen dependent and that androgen dependency occurs via prostatic stromal AR but not epithelial AR. Utilizing tissue recombination models of [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation de Stat3 dans les cellules souches urothéliales induit le développement d'une forme invasive de cancer de la vessie

Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer

Ho, Philip Levy ; Lay, Erica J ; Jian, Weiguo ; Parra, Diana ; Chan, Keith Syson

Two subtypes of human bladder cancer, non-invasive papillary and muscle-invasive cancer, develop through independent pathologic and molecular pathways. Human invasive bladder cancer frequently develops without prior clinical evidence of a non-invasive tumor stage. However, an animal model that recapitulates this unique clinical progression of invasive bladder cancer has not yet been developed. In this study we created a novel transgenic mouse model of invasive bladder cancer by targeting an [...]

A partir de travaux portant sur des échantillons tumoraux prélevés sur 4 patients atteints d'un carcinome à cellules rénales, cette étude évalue la capacité d'une méthode de séquençage profond, appelée deepSNV, pour détecter et quantifier des variants à simple nucléotide dans des populations cellulaires tumorales

Reliable detection of subclonal single-nucleotide variants in tumour cell populations

Gerstung, Moritz ; Beisel, Christian ; Rechsteiner, Markus ; Wild, Peter ; Schraml, Peter ; Moch, Holger ; Beerenwinkel, Niko

According to the clonal evolution model, tumour growth is driven by competing subclones in somatically evolving cancer cell populations, which gives rise to genetically heterogeneous tumours. Here we present a comparative targeted deep-sequencing approach combined with a customised statistical algorithm, called deepSNV, for detecting and quantifying subclonal single-nucleotide variants in mixed populations. We show in a rigorous experimental assessment that our approach is capable of detecting [...]

Menée initialement sur 214 échantillons tumoraux prélevés sur des patientes atteintes d'un carcinome ovarien, puis sur 3 155 échantillons tumoraux de divers types de cancer, cette étude évalue la faisabilité d'une méthode de quantification des anomalies somatiques de l'ADN

Absolute quantification of somatic DNA alterations in human cancer

Carter, Scott L. ; Cibulskis, Kristian ; Helman, Elena ; McKenna, Aaron ; Shen, Hui ; Zack, Travis ; Laird, Peter W. ; Onofrio, Robert C. ; Winckler, Wendy ; Weir, Barbara A. ; Beroukhim, Rameen ; Pellman, David ; Levine, Douglas A. ; Lander, Eric S. ; Meyerson, Matthew ; Getz, Gad

We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset [...]