A partir de prélèvements de l'épithélium normal de l'œsophage chez 9 donneurs (âge : de 20 à 75 ans), cette étude identifie la présence croissante, avec l'âge, de populations clonales présentant des mutations dans 14 gènes associés au cancer

Somatic mutant clones colonize the human esophagus with age

Martincorena, Inigo ; Fowler, Joanna C. ; Wabik, Agnieszka ; Lawson, Andrew R. J. ; Abascal, Federico ; Hall, Michael W. J. ; Cagan, Alex ; Murai, Kasumi ; Mahbubani, Krishnaa ; Stratton, Michael R. ; Fitzgerald, Rebecca C. ; Handford, Penny A. ; Campbell, Peter J. ; Saeb-Parsy, Kourosh ; Jones, Philip H.

The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en supprimant la réparation des cassures double-brin de l'ADN par recombinaison homologue, une enzyme nucléaire (cGAS) favorise la croissance tumorale

Nuclear cGAS suppresses DNA repair and promotes tumorigenesis

Liu, Haipeng ; Zhang, Haiping ; Wu, Xiangyang ; Ma, Dapeng ; Wu, Juehui ; Wang, Lin ; Jiang, Yan ; Fei, Yiyan ; Zhu, Chenggang ; Tan, Rong ; Jungblut, Peter ; Pei, Gang ; Dorhoi, Anca ; Yan, Qiaoling ; Zhang, Fan ; Zheng, Ruijuan ; Liu, Siyu ; Liang, Haijiao ; Liu, Zhonghua ; Yang, Hua ; Chen, Jianxia ; Wang, Peng ; Tang, Tianqi ; Peng, Wenxia ; Hu, Zhangsen ; Xu, Zhu ; Huang, Xiaochen ; Wang, Jie ; Li, Haohao ; Zhou, Yilong ; Liu, Feng ; Yan, Dapeng ; Kaufmann, Stefan H. E. ; Chen, Chang ; Mao, Zhiyong ; Ge, Baoxue

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING–IRF3–type I IFN signalling cascade. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous [...]

Cet article passe en revue les travaux récents sur le rôle de longs ARNs non codants dans le processus métastatique

Molecular Mechanisms of Long Noncoding RNAs-medicated Cancer Metastasis

Li, Yajuan ; Egranov, Sergey D. ; Yang, Liuqing ; Lin, Chunru

Cancer metastasis is a multistep process that requires cancer cells to leave the primary site, survive in the blood stream, and finally colonize at a distant organ. It is the major cause of cancer morbidity and mortality. The organ specific colonization requires close interaction and communication between cancer cells and host organs. Non-coding RNAs represent the majority of the transcriptome, with long non-coding RNAs (lncRNAs) making up a significant proportion. It has been suggested that [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, via le transfert d'ARN par des vésicules extracellulaires à des cellules de l'os, des cellules tumorales de la prostate favorisent le processus métastatique

Communication of prostate cancer cells with bone cells via extracellular vesicle RNA; a potential mechanism of metastasis

Probert, C. ; Dottorini, T. ; Speakman, A. ; Hunt, S. ; Nafee, T. ; Fazeli, A. ; Wood, S. ; Brown, J. E. ; James, V.

The role of extracellular vesicles (EVs) as vehicles for cell-to-cell communication between a tumour and its environment is a relatively new concept. The hypothesis that EVs may be critical in co-opting tissues by tumours to generate distant metastatic niches is particularly pertinent to prostate cancer (PCa), where metastatic-tropism to bone predominates over other tissue types. The potential role of EVs as a means of communication between PCa cells and cells of the bone stroma such as [...]

Menée in vitro et in vivo sur des modèles de cancer du sein, cette étude met en évidence des mécanismes par lesquels, en contradiction avec des résultats antérieurs, le long ARN non codant MALAT1 supprime le processus métastatique

Long noncoding RNA MALAT1 suppresses breast cancer metastasis

Kim, Jongchan ; Piao, Hai-long ; Kim, Beom-Jun ; Yao, Fan ; Han, Zhenbo ; Wang, Yumeng ; Xiao, Zhenna ; Siverly, Ashley N. ; Lawhon, Sarah E. ; Ton, Baochau N. ; Lee, Hyemin ; Zhou, Zhicheng ; Gan, Boyi ; Nakagawa, Shinichi ; Ellis, Matthew J. ; Liang, Han ; Hung, Mien-Chie ; You, M. James ; Sun, Yutong ; Ma, Li

MALAT1 has previously been described as a metastasis-promoting long noncoding RNA (lncRNA). We show here, however, that targeted inactivation of the Malat1 gene in a transgenic mouse model of breast cancer, without altering the expression of its adjacent genes, promotes lung metastasis, and that this phenotype can be reversed by genetic add-back of Malat1. Similarly, knockout of MALAT1 in human breast cancer cells induces their metastatic ability, which is reversed by re-expression of Malat1. [...]

Menée à l'aide de xénogreffes de lignées cellulaires de glioblastome multiforme sur des modèles murins, cette étude identifie un ensemble de séquences amplificatrices et de facteurs de transcription associés à différents sous-types de la maladie

Chromatin run-on and sequencing maps the transcriptional regulatory landscape of glioblastoma multiforme

Chu, Tinyi ; Rice, Edward J. ; Booth, Gregory T. ; Salamanca, H. Hans ; Wang, Zhong ; Core, Leighton J. ; Longo, Sharon L. ; Corona, Robert J. ; Chin, Lawrence S. ; Lis, John T. ; Kwak, Hojoong ; Danko, Charles G.

The human genome encodes a variety of poorly understood RNA species that remain challenging to identify using existing genomic tools. We developed chromatin run-on and sequencing (ChRO-seq) to map the location of RNA polymerase for almost any input sample, including samples with degraded RNA that are intractable to RNA sequencing. We used ChRO-seq to map nascent transcription in primary human glioblastoma (GBM) brain tumors. Enhancers identified in primary GBMs resemble open chromatin in the [...]