Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels l'ajout d'un (ou plusieurs) chromosome(s) favorise une instabilité génomique susceptible de contribuer au développement d'une tumeur

The presence of extra chromosomes leads to genomic instability

Passerini, Verena ; Ozeri-Galai, Efrat ; de Pagter, Mirjam S. ; Donnelly, Neysan ; Schmalbrock, Sarah ; Kloosterman, Wigard P. ; Kerem, Batsheva ; Storchova, Zuzana

Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns [...]

A partir d'échantillons tumoraux prélevés sur 21 patients atteints d'un carcinome rénal à cellules claires dont la tumeur est à double composante sarcomatoïde et carcinomateuse, cette étude identifie un ensemble de gènes impliqués dans la dé-différentiation de composantes carcinomateuses pour former les éléments sarcomatoïdes

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Bi, Mark ; Zhao, Siming ; Said, Jonathan W. ; Merino, Maria J. ; Adeniran, Adebowale J. ; Xie, Zuoquan ; Nawaf, Cayce B. ; Choi, Jaehyuk ; Belldegrun, Arie S. ; Pantuck, Allan J. ; Kluger, Harriet M. ; Bilgüvar, Kaya ; Lifton, Richard P. ; Shuch, Brian

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 [...]

Menée à l'aide de modèles murins de cancer du côlon ou du foie, cette étude met en évidence des mécanismes par lesquels, en stimulant la transcription de plusieurs gènes, la méthyltransférase Smyd3 favorise le développement d'une tumeur

Smyd3 Is a Transcriptional Potentiator of Multiple Cancer-Promoting Genes and Required for Liver and Colon Cancer Development

Sarris, Michalis E ; Moulos, Panagiotis ; Haroniti, Anna ; Giakountis, Antonis ; Talianidis, Iannis

Smyd3 is a protein methyltransferase implicated in cancer development. Here we show that Smyd3 expression in mice is required for chemically induced liver and colon cancer formation. In these organs Smyd3 functions in the nucleus, stimulating the transcription of several key regulators involved in cell proliferation, epithelial-mesenchymal transition, the JAK/Stat3 oncogenic pathway, as well as the Myc and Ctnnb1 oncogenes. Smyd3 interacts with H3K4Me3-modified histone tails, which facilitates [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en favorisant l'augmentation du nombre de lymphocytes T régulateurs, un gène KRAS muté permet aux cellules tumorales d'échapper à la surveillance du système immunitaire

Mutant KRAS conversion of conventional T cells into regulatory T cells

Zdanov, Stephanie ; Mandapathil, Magis ; Abu Eid, Rasha ; Adamson-Fadeyi, Saudat ; Wilson, Willie ; Qian, Jiahua ; Carnie, Andrea ; Tarasova, Nadya ; Mkrtichyan, Mikayel ; Berzofsky, Jay A ; Whiteside, Theresa L ; Khleif, Samir N.

Constitutive activation of the KRAS oncogene in human malignancies is associated with aggressive tumor growth and poor prognosis. Similar to other oncogenes, KRAS acts in a cell-intrinsic manner to affect tumor growth or survival. However, we describe here a different, cell-extrinsic, mechanism through which mutant KRAS contributes to tumor development. Tumor cells carrying mutated KRAS induced highly suppressive T cells, and silencing KRAS reversed this effect. Overexpression of the mutant [...]

Menée à l'aide de modèles murins de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels la perte du gène Ets2 et de divers autres gènes, situés à l'intérieur de la région génomique délimitée par les gènes TMPRSS2 et ERG, favorise la progression tumorale

Deletion of interstitial genes between TMPRSS2 and ERG promotes prostate cancer progression

Linn, Douglas E. ; Penney, Kathryn L. ; Bronson, Roderick T. ; Mucci, Lorelei A. ; Li, Zhe

TMPRSS2-ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ~3Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS22-ERG insertion or deletion events in the background of [...]

Menée à l'aide de modèles murins de cancer du sein, cette étude met en évidence les performances d'une technique d'imagerie pour visualiser, à l'échelle cellulaire, l'activation d'un programme de transition épithélio-mésenchymateuse

In vivo visualization and characterization of epithelial-mesenchymal transition in breast tumors

Zhao, Zhen ; Zhu, Xiaoping ; Cui, Kemi ; Mancuso, James ; Federley, Richard ; Fischer, Kari ; Teng, Gaojun ; Mittal, Vivek ; Gao, Dingcheng ; Zhao, Hong ; Wong, Stephen TC

The activation of the epithelial-to-mesenchymal transition (EMT) program is a critical step in cancer progression and metastasis, but visualization of this process at the single cell level, especially in vivo, remains challenging. We established an in vivo approach to track the fate of tumor cells based on a novel EMT-driven fluorescent color switching breast cancer mouse model and intravital two-photon laser scanning microscopy. Specifically, the MMTV-PyMT, Rosa26-RFP-GFP, and Fsp1-Cre triple [...]