Menée initialement sur 10 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un chondrosarcome, puis validée sur une cohorte complémentaire de 49 patients atteints d'un chondrosarcome et 41 patients atteints d'un enchondrome, cette étude identifie notamment de fréquentes mutations somatiques du gène COL2A1

Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma

Totoki, Yasushi ; Yoshida, Akihiko ; Hosoda, Fumie ; Nakamura, Hiromi ; Hama, Natsuko ; Ogura, Koichi ; Yoshida, Aki ; Fujiwara, Tomohiro ; Arai, Yasuhito ; Toguchida, Junya ; Tsuda, Hitoshi ; Miyano, Satoru ; Kawai, Akira ; Shibata, Tatsuhiro

Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with detailed information on molecular alterations, including potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of ten primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of pathological subtype or the presence of IDH1 mutation and unique [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes de nature métabolique par lesquels, en activant l'expression de la sirtuine SIRT6, le gène suppresseur de tumeurs p53 régule de façon négative la néoglucogenèse

Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion

Zhang, Ping ; Tu, Bo ; Wang, Hua ; Cao, Ziyang ; Tang, Ming ; Zhang, Chaohua ; Gu, Bo ; Li, Zhiming ; Wang, Lina ; Yang, Yang ; Zhao, Ying ; Wang, Haiying ; Luo, Jianyuan ; Deng, Chu-Xia ; Gao, Bin ; Roeder, Robert G. ; Zhu, Wei-Guo

In mammalian cells, tumor suppressor p53 plays critical roles in the regulation of glucose metabolism, including glycolysis and oxidative phosphorylation, but whether and how p53 also regulates gluconeogenesis is less clear. Here, we report that p53 efficiently down-regulates the expression of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), which encode rate-limiting enzymes in gluconeogenesis. Cell-based assays demonstrate the p53-dependent nuclear exclusion of [...]

Menée à l'aide de modèles murins, cette étude identifie un groupe de gènes qui, en réprimant la signalisation FGFR, exercent une fonction de suppresseur de tumeurs dans les carcinomes épidermoïdes du poumon

A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors that Repress FGFR Signaling

Lin, Ling ; Chamberlain, Lynn ; Pak, Magnolia L. ; Nagarajan, Arvindhan ; Gupta, Romi ; Zhu, Lihua J. ; Wright, Casey M ; Fong, Kwun M ; Wajapeyee, Narendra ; Green, Michael R.

To discover new tumor suppressor genes (TSGs), we developed a functional genomics approach in which immortalized but non-tumorigenic cells were stably transduced with large-scale short hairpin RNA (shRNA) pools and tested for tumor formation in mice. Identification of shRNAs in resulting tumors revealed candidate TSGs, which were validated experimentally and by analyzing expression in human tumor samples. Using this approach, we identified 24 TSGs that were significantly down-regulated in human [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels des thrombocytes favorisent la formation de niches métastatiques précoces

Platelets guide the formation of early metastatic niches

Labelle, Myriam ; Begum, Shahinoor ; Hynes, Richard O.

During metastasis, host cells are recruited to disseminated tumor cells to form specialized microenvironments (“niches”) that promote metastatic progression, but the mechanisms guiding the assembly of these niches are largely unknown. Tumor cells may autonomously recruit host cells or, alternatively, host cell-to-host cell interactions may guide the formation of these prometastatic microenvironments. Here, we show that platelet-derived rather than tumor cell-derived signals are required for the [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via la polarisation des macrophages associés aux tumeurs, l'acide lactique produit par les cellules tumorales favorise la croissance tumorale

Functional polarization of tumour-associated macrophages by tumour-derived lactic acid

Colegio, Oscar R. ; Chu, Ngoc-Quynh ; Szabo, Alison L. ; Chu, Thach ; Rhebergen, Anne Marie ; Jairam, Vikram ; Cyrus, Nika ; Brokowski, Carolyn E. ; Eisenbarth, Stephanie C. ; Phillips, Gillian M. ; Cline, Gary W. ; Phillips, Andrew J. ; Medzhitov, Ruslan

Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their ‘client cells’: namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated [...]

Menée à l'aide de modèes murins, cette étude met en évidence des mécanismes permettant de rendre compte du rôle de la circulation sanguine dans le processus métastatique d'une tumeur ovarienne

Hematogenous Metastasis of Ovarian Cancer: Rethinking Mode of Spread

Pradeep, Sunila ; Kim, Seung W ; Wu, Sherry Y ; Nishimura, Masato ; Chaluvally-Raghavan, Pradeep ; Miyake, Takahito ; Pecot, Chad V ; Kim, Sun-Jin ; Choi, Hyun Jin ; Bischoff, Farideh Z ; Mayer, Julie Ann ; Huang, Li ; Nick, Alpa M ; Hall, Carolyn S ; Rodriguez-Aguayo, Cristian ; Zand, Behrouz ; Dalton, Heather J ; Arumugam, Thiruvengadam ; Lee, Ho Jeong ; Han, Hee Dong ; Cho, Min Soon ; Rupaimoole, Rajesha ; Mangala, Lingegowda S ; Sehgal, Vasudha ; Oh, Sang Cheul ; Liu, Jinsong ; Lee, Ju-Seog ; Coleman, Robert L ; Ram, Prahlad ; Lopez-Berestein, Gabriel ; Fidler, Isaiah J ; Sood, Anil K

Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la surexpression de la protéine kinase MAP2K4 favorise le processus métastatique d'un cancer de la prostate

Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4) Promotes Human Prostate Cancer Metastasis

Pavese, Janet M. ; Ogden, Irene M. ; Voll, Eric A. ; Huang, Xiaoke ; Xu, Li ; Jovanovic, Borko ; Bergan, Raymond C.

Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4's role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress [...]

Menée à l'aide d'un modèle murin présentant la mutation R1715H du gène p53 et sur des lignées cellulaires d'ostéosarcome humain, cette étude met en évidence des mécanismes par lesquels une phospholipase, Pla2g16, favorise le processus métastatique

Pla2g16 phospholipase mediates gain-of-function activities of mutant p53

Xiong, Shunbin ; Tu, Huolin ; Kollareddy, Madhusudhan ; Pant, Vinod ; Li, Qin ; Zhang, Yun ; Jackson, James G. ; Suh, Young-Ah ; Elizondo-Fraire, Ana C. ; Yang, Peirong ; Chau, Gilda ; Tashakori, Mehrnoosh ; Wasylishen, Amanda R. ; Ju, Zhenlin ; Solomon, Hilla ; Rotter, Varda ; Liu, Bin ; El-Naggar, Adel K. ; Donehower, Lawrence A. ; Martinez, Luis Alfonso ; Lozano, Guillermina

p53R172H/+ mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53+/− mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53R172H/+ mice with metastasis to osteosarcomas from p53+/− mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes [...]

Cet article passe en revue les travaux récents sur le rôle du micro-environnement tumoral dans les lymphomes à cellules B

The tumour microenvironment in B cell lymphomas

Scott, David W. ; Gascoyne, Randy D.

B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en régulant la formation de tissus adipeux bruns, l'expression de la protéine PTHrP par les cellules tumorales favorise l'apparition d'une cachexie

Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia

Kir, Serkan ; White, James P. ; Kleiner, Sandra ; Kazak, Lawrence ; Cohen, Paul ; Baracos, Vickie E. ; Spiegelman, Bruce M.

Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung [...]

Menée sur des échantillons de tissu tumoral et de tissu péritumoral prélevés sur des patients attients d'un gliome, cette étude française met en évidence le rôle joué par la signalisation GABA dans les manifestations épileptiques associées à la maladie

Cortical GABAergic excitation contributes to epileptic activities around human glioma

Pallud, Johan ; Le Van Quyen, Michel ; Bielle, Franck ; Pellegrino, Christophe ; Varlet, Pascale ; Labussiere, Marianne ; Cresto, Noémie ; Dieme, Marie-Joseph ; Baulac, Michel ; Duyckaerts, Charles ; Kourdougli, Nazim ; Chazal, Geneviève ; Devaux, Bertrand ; Rivera, Claudio ; Miles, Richard ; Capelle, Laurent ; Huberfeld, Gilles

Brain gliomas are highly epileptogenic. Excitatory glutamatergic mechanisms are involved in the generation of epileptic activities in the neocortex surrounding gliomas. However, chloride homeostasis is known to be perturbed in glioma cells. Thus, the contribution of γ-aminobutyric acidergic (GABAergic) mechanisms that depend on intracellular chloride merits closer study. We studied the occurrence, networks, cells, and signaling basis of epileptic activities in neocortical slices from the [...]