Menée sur 74 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un neuroblastome, cette étude identifie la présence d'altérations des gènes de remodelage de la chromatine, ARID1A et ARID1B, en association avec un pronostic défavorable

Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

Sausen, Mark ; Leary, Rebecca J. ; Jones, Sian ; Wu, Jian ; Reynolds, C. Patrick ; Liu, Xueyuan ; Blackford, Amanda ; Parmigiani, Giovanni ; Diaz, Luis A. ; Papadopoulos, Nickolas ; Vogelstein, Bert ; Kinzler, Kenneth W. ; Velculescu, Victor E. ; Hogarty, Michael D.

Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma, we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases) and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average, each tumor had 19 somatic alterations in coding genes (range of 3–70). Among genes not previously known to be [...]

Cet article passe en revue les travaux récents sur le rôle de l'axe transcriptionnel PGC-1/ERR, en interaction avec divers oncogènes, dans la reprogrammation métabolique des cellules cancéreuses

The PGC-1/ERR signaling axis in cancer

Deblois, G. ; St-Pierre, J. ; Giguere, V.

Proliferating cells need to produce a large amount of energy and, at the same time, need to maintain a constant supply of biosynthetic precursors of macromolecules that are used as building blocks for generating new cells. Indeed, many cancer cells undergo a switch from mitochondrial to glycolytic metabolism and display a truncated tricarboxylic acid cycle to match these specific metabolic requirements of proliferation. Understanding the mechanisms by which cancer cells reprogram various [...]

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme impliquant le gène Sox9 dans la formation de lésions prénéoplasiques d'un adénocarcinome canalaire du pancréas

Identification of Sox9-Dependent Acinar-to-Ductal Reprogramming as the Principal Mechanism for Initiation of Pancreatic Ductal Adenocarcinoma

Kopp, Janel L ; von Figura, Guido ; Mayes, Erin ; Liu, Fen-Fen ; Dubois, Claire L ; Morris, John P ; Pan, Fong Cheng ; Akiyama, Haruhiko ; Wright, Christopher V E. ; Jensen, Kristin ; Hebrok, Matthias ; Sander, Maike

Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel la molécule de surface cellulaire CD44 favorise la prolifération des cellules tumorales d'un adénocarcinome du poumon lié à la mutation G12D du gène KRAS

CD44 promotes Kras-dependent lung adenocarcinoma

Zhao, P. ; Damerow, M. S. ; Stern, P. ; Liu, A. H. ; Sweet-Cordero, A. ; Siziopikou, K. ; Neilson, J. R. ; Sharp, P. A. ; Cheng, C.

Kras-induced non-small-cell lung adenocarcinoma is the major subtype of lung cancers and is associated with poor prognosis. Using a lung cancer mouse model that expresses a cre-mediated KrasG12D mutant, we identified a critical role for the cell surface molecule CD44 in mediating cell proliferation downstream of oncogenic Kras signaling. The deletion of CD44 attenuates lung adenocarcinoma formation and prolongs the survival of these mice. Mechanistically, CD44 is required for the activation of [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme de nature épigénétique par lequel, en activant la signalisation Wnt, la surexpression d'une protéine de remodelage de la chromatine dans le stroma induit la formation d'un adénocarcinome de la prostate

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Zong, Yang ; Huang, Jiaoti ; Sankarasharma, Devipriya ; Morikawa, Teppei ; Fukayama, Masashi ; Epstein, Jonathan I. ; Chada, Kiran K. ; Witte, Owen N.

Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AT-hook 2) an epigenetic regulator, to modify [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le facteur de transcription Twist1 dans la régulation de la transition épithélio-mésenchymateuse et le processus métastatique d'un carcinome épidermoïde

Spatiotemporal Regulation of Epithelial-Mesenchymal Transition Is Essential for Squamous Cell Carcinoma Metastasis

Tsai, Jeff H ; Donaher, Joana Liu ; Murphy, Danielle A ; Chau, Sandra ; Yang, Jing

Epithelial-mesenchymal transition (EMT) is implicated in converting stationary epithelial tumor cells into motile mesenchymal cells during metastasis. However, the involvement of EMT in metastasis is still controversial, due to the lack of a mesenchymal phenotype in human carcinoma metastases. Using a spontaneous squamous cell carcinoma mouse model, we show that activation of the EMT-inducing transcription factor Twist1 is sufficient to promote carcinoma cells to undergo EMT and disseminate [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel le facteur Prrx1, qui induit une transition épithélio-mésenchymateuse dans les embryons et les cellules cancéreuses, régule le processus métastatique

Metastatic Colonization Requires the Repression of the Epithelial-Mesenchymal Transition Inducer Prrx1

Ocaña, Oscar H ; Córcoles, Rebeca ; Fabra, Ángels ; Moreno-Bueno, Gema ; Acloque, Hervé ; Vega, Sonia ; Barrallo-Gimeno, Alejandro ; Cano, Amparo ; Nieto, M.  Angela

The epithelial-mesenchymal transition (EMT) is required in the embryo for the formation of tissues for which cells originate far from their final destination. Carcinoma cells hijack this program for tumor dissemination. The relevance of the EMT in cancer is still debated because it is unclear how these migratory cells colonize distant tissues to form macrometastases. We show that the homeobox factor Prrx1 is an EMT inducer conferring migratory and invasive properties. The loss of Prrx1 is [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en régulant de façon différentielle les niveaux de deux cadhérines, le gène B-RAF muté favorise le processus invasif d'un mélanome

Mutant B-RAF regulates a Rac-dependent cadherin switch in melanoma

Monaghan-Benson, E. ; Burridge, K.

The ability of cells to invade into the dermis is a critical event in the development of cutaneous melanoma and ultimately an indicator of poor prognosis. However, the molecular events surrounding the acquisition of this invasive phenotype remain incompletely understood. Mutations in B-RAF are frequent in melanoma and are known to regulate the invasive phenotype. In this study, we sought to determine the molecular mechanisms controlling melanoma invasion. We found that mutant B-RAF signaling [...]

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme impliquant le facteur de transcription COUP-TFII et la signalisation TGF-

COUP-TFII inhibits TGF-

Qin, Jun ; Wu, San-Pin ; Creighton, Chad J. ; Dai, Fangyan ; Xie, Xin ; Cheng, Chiang-Min ; Frolov, Anna ; Ayala, Gustavo ; Lin, Xia ; Feng, Xin-Hua ; Ittmann, Michael M. ; Tsai, Shaw-Jenq ; Tsai, Ming-Jer ; Tsai, Sophia Y.

Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en interaction avec la signalisation du gène ANGPTL4, le récepteur

Inverse

Adhikary, T. ; Brandt, D. T. ; Kaddatz, K. ; Stockert, J. ; Naruhn, S. ; Meissner, W. ; Finkernagel, F. ; Obert, J. ; Lieber, S. ; Scharfe, M. ; Jarek, M. ; Toth, P. M. ; Scheer, F. ; Diederich, W. E. ; Reinartz, S. ; Grosse, R. ; Muller-Brusselbach, S. ; Muller, R.

Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor