Menée sur 239 échantillons prélevés sur des patients atteints d'un lymphome, cette étude identifie la présence fréquente de mutations du gène RHOA chez les patients atteints d'un lymphome T angioimmunoblastique

A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma

Yoo, Hae Yong ; Sung, Min Kyung ; Lee, Seung Ho ; Kim, Sangok ; Lee, Haeseung ; Park, Seongjin ; Kim, Sang Cheol ; Lee, Byungwook ; Rho, Kyoohyoung ; Lee, Jong-Eun ; Cho, Kwang-Hwi ; Kim, Wankyu ; Ju, Hyunjung ; Kim, Jaesang ; Kim, Seok Jin ; Kim, Won Seog ; Lee, Sanghyuk ; Ko, Young Hyeh

The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly17Val) using exome and transcriptome sequencing of samples from individuals with AITL. Further examination of the RHOA mutation encoding p.Gly17Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma. We [...]

Menée sur 287 échantillons tumoraux prélevés sur des patients atteints d'un mélanome cutané, cette étude met en évidence de fréquentes mutations dans la séquence promotrice du gène codant pour la sous-unité protéique de la télomérase (TERT)

Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma

Heidenreich, Barbara ; Nagore, Eduardo ; Rachakonda, P. Sivaramakrishna ; Garcia-Casado, Zaida ; Requena, Celia ; Traves, Victor ; Becker, Jürgen ; Soufir, Nadem ; Hemminki, Kari ; Kumar, Rajiv

We previously reported a disease segregating causal germline mutation in a melanoma family and recurrent somatic mutations in metastasized tumours from unrelated patients in the core promoter region of the telomerase reverse transcriptase (TERT) gene. Here we show that the TERT promoter mutations, besides causing an increased gene expression, associate with increased patient age, increased Breslow thickness and tumour ulceration in 287 primary melanomas. The mutations are more frequent at both [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant l'élongation de l'ARN polymérase II, le gène ZMYND11 exerce une fonction de suppresseur de tumeurs

ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression

Wen, Hong ; Li, Yuanyuan ; Xi, Yuanxin ; Jiang, Shiming ; Stratton, Sabrina ; Peng, Danni ; Tanaka, Kaori ; Ren, Yongfeng ; Xia, Zheng ; Wu, Jun ; Li, Bing ; Barton, Michelle C. ; Li, Wei ; Li, Haitao ; Shi, Xiaobing

Recognition of modified histones by ‘reader’ proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is [...]

Cet article passe en revue les travaux récents sur les fonctions attribuées au récepteur à activité tyrosine kinase RET dans le développement et la progression d'un cancer, notamment les cancers de la thyroïde, du poumon, du sein et du pancréas

RET revisited: expanding the oncogenic portfolio

Mulligan, Lois M.

The RET receptor tyrosine kinase is crucial for normal development but also contributes to pathologies that reflect both the loss and the gain of RET function. Activation of RET occurs via oncogenic mutations in familial and sporadic cancers - most notably, those of the thyroid and the lung. RET has also recently been implicated in the progression of breast and pancreatic tumours, among others, which makes it an attractive target for small-molecule kinase inhibitors as therapeutics. However, [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via la protéine YAP, la voie de signalisation Hippo régule la sous-expression de micro-ARNs dans les cellules tumorales en fonction de la densité cellulaire

Hippo Signaling Regulates Microprocessor and Links Cell-Density-Dependent miRNA Biogenesis to Cancer

Mori, Masaki ; Triboulet, Robinson ; Mohseni, Morvarid ; Schlegelmilch, Karin ; Shrestha, Kriti ; Camargo, Fernando D ; Gregory, Richard I

Global downregulation of microRNAs (miRNAs) is commonly observed in human cancers and can have a causative role in tumorigenesis. The mechanisms responsible for this phenomenon remain poorly understood. Here, we show that YAP, the downstream target of the tumor-suppressive Hippo-signaling pathway regulates miRNA biogenesis in a cell-density-dependent manner. At low cell density, nuclear YAP binds and sequesters p72 (DDX17), a regulatory component of the miRNA-processing machinery. At high cell [...]

Menée in vitro et à partir d'échantillons tumoraux prélevés sur 29 patients atteints d'un cancer du poumon, cette étude met en évidence des mécanismes par lesquels un micro-ARN induit par le facteur TGF-β, miR-183, réprime l'expression de la protéine DAP12 dans les cellules NK du micro-environnement tumoral

TGF-β–inducible microRNA-183 silences tumor-associated natural killer cells

Donatelli, Sarah S. ; Zhou, Jun-Min ; Gilvary, Danielle L. ; Eksioglu, Erika A. ; Chen, Xianghong ; Cress, W. Douglas ; Haura, Eric B. ; Schabath, Matthew B. ; Coppola, Domenico ; Wei, Sheng ; Djeu, Julie Y.

Transforming growth factor β1 (TGF-β), enriched in the tumor microenvironment and broadly immunosuppressive, inhibits natural killer (NK) cell function by yet-unknown mechanisms. Here we show that TGF-β–treated human NK cells exhibit reduced tumor cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of activating killer Ig-like receptor 2DS4 and NKp44, despite intact cytoplasmic stores of these receptors. Instead, TGF-β [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une activation autocrine de la signalisation FGF favorise le développement d'une tumeur cutanée associée à la perte du gène suppresseur de tumeurs PTEN

Pten Loss Induces Autocrine FGF Signaling to Promote Skin Tumorigenesis

Hertzler-Schaefer, Kristina ; Mathew, Grinu ; Somani, Ally-Khan ; Tholpady, Sunil ; Kadakia, Madhavi P ; Chen, Yiping ; Spandau, Dan F ; Zhang, Xin

Inactivation of the Pten tumor suppressor negatively regulates the PI3K-mTOR pathway. In a model of cutaneous squamous cell carcinoma (SCC), we demonstrate that deletion of Pten strongly elevates Fgf10 protein levels without increasing Fgf10 transcription in vitro and in vivo. The translational activation of Fgf10 by Pten deletion is reversed by genetic disruption of the mTORC1 complex, which also prevents skin tumorigenesis in Pten mutants. We further show that ectopic expression of Fgf10 [...]

Menée à l'aide d'un modèle murin d'adénocarcinome pulmonaire induit par un gène K-Ras muté, cette étude montre qu'il existe plusieurs voies cellulaires menant à la formation d'une tumeur et que la cellule d'origine en influence le phénotype histologique

Multiple cells-of-origin of mutant K-Ras–induced mouse lung adenocarcinoma

Sutherland, Kate D. ; Song, Ji-Ying ; Kwon, Min Chul ; Proost, Natalie ; Zevenhoven, John ; Berns, Anton

Much controversy surrounds the cell-of-origin of mutant K-Ras (K-RasG12D)–induced lung adenocarcinoma. To shed light on this issue, we have used technology that enables us to conditionally target K-RasG12D expression in Surfactant Protein C (SPC)+ alveolar type 2 cells and in Clara cell antigen 10 (CC10)+ Clara cells by use of cell-type–restricted recombinant Adeno-Cre viruses. Experiments were performed both in the presence and absence of the tumor suppressor gene p53, enabling us to assess [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels une activation de la signalisation Wnt/β-caténine, dans les lymphocytes T régulateurs et/ou les lymphocytes T effecteurs, favorise le déveoppement d'un cancer du côlon

β-Catenin Promotes Colitis and Colon Cancer Through Imprinting of Proinflammatory Properties in T Cells

Keerthivasan, Shilpa ; Aghajani, Katayoun ; Dose, Marei ; Molinero, Luciana ; Khan, Mohammad W. ; Venkateswaran, Vysak ; Weber, Christopher ; Emmanuel, Akinola Olumide ; Sun, Tianjao ; Bentrem, David J. ; Mulcahy, Mary ; Keshavarzian, Ali ; Ramos, Elena M. ; Blatner, Nichole ; Khazaie, Khashayarsha ; Gounari, Fotini

The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (TH17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. [...]

Menée in vitro et n vivo, cette étude met en évidence des mécanismes par lesquels, en favorisant la dégradation et l'ubiquitination de la protéine p53, la protéine UBE4B exerce une fonction oncogénique dans le cancer du sein

Regulation of p53 Level by UBE4B in Breast Cancer

Zhang, Ying ; Lv, Yanrong ; Zhang, Yongyang ; Gao, Haidong

p53 is possibly the most important mammalian tumor suppressor and it is mutated or lost in more than half of all human cancers. The stability of p53 is primarily determined by the RING domain E3 ubiquitin ligase Hdm2, which targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. UBE4B has been shown to physically interact with p53 and Hdm2 and to negatively regulate p53 stability and function. However, no one has determined [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en réprimant la transcription d'un micro-ARN, le gène EMSY exerce une fonction oncogénique dans le cancer du sein

The Breast Cancer Oncogene EMSY Represses Transcription of Antimetastatic microRNA miR-31

Viré, Emmanuelle ; Curtis, Christina ; Davalos, Veronica ; Git, Anna ; Robson, Samuel ; Villanueva, Alberto ; Vidal, August ; Aparicio, Samuel ; Esteller, Manel ; Caldas, Carlos ; Kouzarides, Tony

Amplification of the EMSY gene in sporadic breast and ovarian cancers is a poor prognostic indicator. Although EMSY has been linked to transcriptional silencing, its mechanism of action is unknown. Here, we report that EMSY acts as an oncogene, causing the transformation of cells in vitro and potentiating tumor formation and metastatic features in vivo. We identify an inverse correlation between EMSY amplification and miR-31 expression, an antimetastatic microRNA, in the METABRIC cohort of [...]

Cet article passe en revue les travaux récents sur l'hétérogénéité cellulaire des tumeurs du pancréas

The Secret Origins and Surprising Fates of Pancreas Tumors

Bailey, Jennifer M. ; DelGiorno, Kathleen E. ; Crawford, Howard C.

Pancreatic ductal adenocarcinoma (PDA) is especially deadly due to its recalcitrance to current therapies. One of the unique qualities of PDA that may contribute to this resistance is a striking plasticity of differentiation states starting at tumor formation and continuing throughout tumor progression, including metastasis. Here we explore the earliest steps of tumor formation and neoplastic progression and how this results in a fascinating cellular heterogeneity that is likely critical for [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par les serpines dans la survie des cellules de métastases cérébrales d'un cancer du sein ou du poumon

Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis

Valiente, Manuel ; Obenauf, Anna C ; Jin, Xin ; Chen, Qing ; Zhang, Xiang H F. ; Lee, Derek J ; Chaft, Jamie E ; Kris, Mark G ; Huse, Jason T ; Brogi, Edi ; Massagué, Joan

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels un récepteur couplé aux protéines G, GALR2, favorise l'angiogenèse tumorale dans les carcinomes épidermoïdes de la tête et du cou

The G-protein Coupled Receptor GALR2 Promotes Angiogenesis in Head and Neck Cancer

Banerjee, Rajat ; Van Tubergen, Elizabeth A. ; Scanlon, Christina S ; Vander Broek, Robert ; Lints, Joel P ; Liu, Min ; Russo, Nickole ; Inglehart, Ronald ; Wang, Yugang ; Polverini, Peter J ; Kirkwood, Keith L. ; D'Silva, Nisha J.

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor patient survival. Galanin Receptor 2 (GALR2) is a G-protein coupled receptor (GPCR) that induces aggressive tumor growth in SCCHN. The objective of this study was to investigate the mechanism by which GALR2 promotes angiogenesis, a critical oncogenic phenotype required for tumor growth. The impact of GALR2 expression on secretion of pro-angiogenic cytokines in multiple SCCHN cell lines was investigated by [...]

Cet article passe en revue les travaux récents sur le développement de la technologie CRISPR ("Clustered, Regularly Intespaced, Short Palindromic Repeat") pour créer de façon ciblée des altérations d'une séquence génomique ou de l'expression de gènes

CRISPR-Cas systems for editing, regulating and targeting genomes

Sander, Jeffry D. ; Joung, J. Keith

Targeted genome editing using engineered nucleases has rapidly gone from being a niche technology to a mainstream method used by many biological researchers. This widespread adoption has been largely fueled by the emergence of the clustered, regularly interspaced, short palindromic repeat (CRISPR) technology, an important new approach for generating RNA-guided nucleases, such as Cas9, with customizable specificities. Genome editing mediated by these nucleases has been used to rapidly, easily [...]