A partir de données portant sur des lignées cellulaires cancéreuses murines et humaines, cette étude analyse les différences entre les taux de mutations somatiques et constitutionnelles observés entre les deux espèces

Differences between germline and somatic mutation rates in humans and mice

Milholland, Brandon ; Dong, Xiao ; Zhang, Lei ; Hao, Xiaoxiao ; Suh, Yousin ; Vijg, Jan

The germline mutation rate has been extensively studied and has been found to vary greatly between species, but much less is known about the somatic mutation rate in multicellular organisms, which remains very difficult to determine. Here, we present data on somatic mutation rates in mice and humans, obtained by sequencing single cells and clones derived from primary fibroblasts, which allows us to make the first direct comparison with germline mutation rates in these two species. The results [...]

A partir de 308 échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude identifie un ensemble de mutations non codantes dans des régions du génome liées à la régulation de l'expression des gènes

Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma

Feigin, Michael E. ; Garvin, Tyler ; Bailey, Peter ; Waddell, Nicola ; Chang, David K. ; Kelley, David R. ; Shuai, Shimin ; Gallinger, steven ; McPherson, John D. ; Grimmond, Sean M. ; Khurana, Ekta ; Stein, Lincoln D. ; Biankin, Andrew V. ; Schatz, Michael C. ; Tuveson, David A.

The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly [...]

Menée in vitro et in vivo sur des modèles de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels la signalisation RET favorise la transformation maligne

RET signaling in prostate cancer

Ban, Kechen ; Feng, Shu ; Shao, Longjiang ; Ittmann, Michael

Purpose: Large diameter perineural prostate cancer is associated with poor outcomes. GDNF, with its co-receptor GFRα1, binds RET and activates downstream pro-oncogenic signaling. Since both GDNF and GFRα1 are secreted by nerves, we examined the role of RET signaling in prostate cancer. Experimental Design: Expression of RET, GDNF and/or GFRα1 was assessed. The impact of RET signaling on proliferation, invasion and soft agar colony formation, perineural invasion and growth in vivo was [...]

Menée in vitro et in vivo sur des modèles de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels deux facteurs de transcription impliqués dans le développement embryonnaire de la prostate, TWIST1 et HOXA9, sont réactivés pendant la croissance tumorale et favorisent le processus métastatique

TWIST1-WDR5-Hottip regulates Hoxa9 chromatin to facilitate prostate cancer metastasis

Malek, Reem ; gajula, Rajendra P. ; Williams, Russell D. ; Nghiem, Belinda ; Simons, Brian W. ; Nugent, Katriana ; Wang, Hailun ; Taparra, Kekoa ; Lemtiri-Chlieh, Ghali ; Yoon, Arum R. ; True, Lawrence ; An, Steven S. ; DeWeese, Theodore L. ; Ross, Ashley E. ; Schaeffer, Edward M. ; Pienta, Kenneth J. ; Hurley, Paula J. ; Morrissey, Colm ; Tran, Phuoc T.

TWIST1 is a transcription factor critical for development which can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are co-expressed in mouse prostate and then silenced post-natally. Here we report that TWIST1 and HOXA9 co-expression are re-activated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like [...]

Cette étude présente un modèle de simulation en réseau impliquant trois voies de signalisation liées à des suppresseurs de tumeurs (régulation de la prolifération cellulaire, activation de p53, induction de l'apoptose) et analyse la réponse dynamique de ce réseau à des signaux de nature oncogénique

Modeling the response of a tumor-suppressive network to mitogenic and oncogenic signals

Tian, Xinyu ; Huang, Bo ; Zhang, Xiao-Peng ; Lu, Mingyang ; Liu, Feng ; Onuchic, José N. ; Wang, Wei

Intrinsic tumor-suppressive mechanisms protect normal cells against aberrant proliferation. Although cellular signaling pathways engaged in tumor repression have been largely identified, how they are orchestrated to fulfill their function still remains elusive. Here, we built a tumor-suppressive network model composed of three modules responsible for the regulation of cell proliferation, activation of p53, and induction of apoptosis. Numerical simulations show a rich repertoire of network [...]