Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une mutation activant la

Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts

Kode, Aruna ; Manavalan, John S. ; Mosialou, Ioanna ; Bhagat, Govind ; Rathinam, Chozha V. ; Luo, Na ; Khiabanian, Hossein ; Lee, Albert ; Murty, Vundavalli V. ; Friedman, Richard ; Brum, Andrea ; Park, David ; Galili, Naomi ; Mukherjee, Siddhartha ; Teruya-Feldstein, Julie ; Raza, Azra ; Rabadan, Raul ; Berman, Ellin ; Kousteni, Stavroula

Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of

Menée sur des échantillons tumoraux prélevés sur 997 patients chinois atteints d'un cancer du poumon, cette étude évalue la présence concomitante de mutations du gène EGFR et de réarrangements ALK et analyse leurs effets sur la réponse au crizotinib et aux inhibiteurs de l'activité tyrosine kinase de l'EGFR

Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation

Yang, Jinji ; Zhang, Xu-Chao ; Su, Jian ; Xu, Chongrui ; Zhou, Qing ; Tian, Hong-Xia ; Xie, Zhi ; Chen, Hua-Jun ; Huang, Yi-Sheng ; Jiang, Ben-Yuan ; Wang, Zhen ; Wang, Bin-Chao ; Yang, Xuening ; Zhong, Wenzhao ; Nie, Qiang ; Liao, Ri-Qiang ; Mok, Tony S.K. ; Wu, Yi-Long

Purpose: We investigated the incidence of concomitant EGFR mutations and ALK rearrangements in Chinese patients with non-small-cell lung cancer (NSCLC), and assessed responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib in such tumors. Experimental Design: We screened 977 consecutive patients with NSCLC for the presence of concomitant EGFR mutations and ALK rearrangements by rapid amplification of cDNA ends-coupled polymerase chain reaction sequencing and fluorescence in situ [...]

Menée à l'aide de cellules tétraploïdes issues de cellules diploïdes de cancer du côlon, cette étude montre que les cellules survivant à un doublement du génome exhibent une tolérance accrue aux anomalies génomiques

Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

Dewhurst, Sally M. ; McGranahan, Nicholas ; Burrell, Rebecca A. ; Rowan, Andrew J. ; Grönroos, Eva ; Endesfelder, David ; Joshi, Tejal ; Mouradov, Dmitri ; Gibbs, Peter ; Ward, Robyn L. ; Hawkins, Nicholas J. ; Szallasi, Zoltan ; Sieber, Oliver M. ; Swanton, Charles

The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the [...]

Menée sur des échantillons tumoraux prélevés sur 99 patientes atteintes d'un cancer du sein, cette étude analyse les mutations de l'ADN mitochondrial et évalue l'association entre les mutations somatiques de l'ADN mitochondrial et la survie des patientes

Mutational patterns in the breast cancer mitochondrial genome, with clinical correlates

McMahon, Sarah ; Laframboise, Thomas

The presence of mitochondrial DNA (mtDNA) mutations in human cancer has long been recognized, but their functional significance has remained obscure. Debate persists as to whether the mutations help drive the tumor, or are bystander events. Here we analyze next-generation mtDNA sequence data from 99 breast cancer patients. High depth coverage enables detection of even low-level heteroplasmic variants, and data from matched normal tissue allows us to distinguish between shifts in heteroplasmy [...]

Menée à l'aide de xénogreffes et sur 177 lignées cellulaires cancéreuses, cette étude met en évidence le rôle joué par la protéine GPX4 dans un mécanisme de mort cellulaire non apoptotique appelé ferroptose

Regulation of Ferroptotic Cancer Cell Death by GPX4

Yang, Wan Seok ; SriRamaratnam, Rohitha ; Welsch, Matthew E ; Shimada, Kenichi ; Skouta, Rachid ; Viswanathan, Vasanthi S ; Cheah, Jaime H ; Clemons, Paul A ; Shamji, Alykhan F ; Clish, Clary B ; Brown, Lewis M ; Girotti, Albert W ; Cornish, Virginia W ; Schreiber, Stuart L ; Stockwell, Brent R

Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown [...]

Cet article suggère que l'augmentation du risque de cancer avec l'âge n'est pas due à l'accumulation de mutations du génome mais au déclin normal du métabolisme oxydant et, notamment au rôle joué par les sirtuines

Geroncogenesis: Metabolic Changes during Aging as a Driver of Tumorigenesis

Wu, Lindsay E ; Gomes, Ana P ; Sinclair, David A

Why does cancer risk increase as we age? Frequently attributed to the multi-hit hypothesis and the time required to accumulate genomic mutations, this question is a matter of ongoing debate. Here, we propose that the normal decline in oxidative metabolism during aging constitutes an early and important hit that drives tumorigenesis. Central to these metabolic changes are the sirtuins, a family of NAD+-dependent deacylases that have evolved as coordinators of physiological responses to nutrient [...]

Menée à l'aide d'ARNs interférents et de modèles murins, cette étude suggère que la myosine de type IIa joue un rôle de suppresseur de tumeurs dans les carcinomes épidermoïdes

Direct in Vivo RNAi Screen Unveils Myosin IIa as a Tumor Suppressor of Squamous Cell Carcinomas

Schramek, Daniel ; Sendoel, Ataman ; Segal, Jeremy P. ; Beronja, Slobodan ; Heller, Evan ; Oristian, Daniel ; Reva, Boris ; Fuchs, Elaine

Mining modern genomics for cancer therapies is predicated on weeding out “bystander” alterations (nonconsequential mutations) and identifying “driver” mutations responsible for tumorigenesis and/or metastasis. We used a direct in vivo RNA interference (RNAi) strategy to screen for genes that upon repression predispose mice to squamous cell carcinomas (SCCs). Seven of our top hits—including Myh9, which encodes nonmuscle myosin IIa—have not been linked to tumor development, yet tissue-specific [...]

Cet article passe en revue une décennie de travaux sur le rôle de suppresseur de tumeurs joué par la protéine CHD5 dans divers types de tumeurs (neuroblastome, gliome, cancers du sein, du côlon, du poumon, de l'ovaire, de la prostate, ...)

Role of CHD5 in Human Cancers: 10 Years Later

Kolla, Venkatadri ; Zhuang, Tiangang ; Higashi, Mayumi ; Naraparaju, Koumudi ; Brodeur, Garrett M.

CHD5 was first identified because of its location on 1p36 in a region of frequent deletion in neuroblastomas. CHD5 (chromodomain–helicase–DNA–binding-5) is the fifth member of a family of chromatin remodeling proteins, and it probably functions by forming a nucleosome remodeling and deacetylation (NuRD) complex that regulates transcription of particular genes. CHD5 is preferentially expressed in the nervous system and testis. On the basis of its position, pattern of expression, and function in [...]

Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence le rôle joué par l'expression du gène IDH2 muté dans le développement et l'entretien d'une leucémie myéloïde aiguë

Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance

Kats, Lev M ; Reschke, Markus ; Taulli, Riccardo ; Pozdnyakova, Olga ; Burgess, Kerri ; Bhargava, Parul ; Straley, Kimberly ; Karnik, Rahul ; Meissner, Alexander ; Small, Donald ; Su, Shinsan M ; Yen, Katharine ; Zhang, Jiangwen ; Pandolfi, Pier Paolo

Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution of mutant IDH proteins to maintenance and progression of AML in vivo is currently unknown. To answer this crucial question we have generated transgenic mice that express IDH2R140Q in an on/off- and [...]

Menée in vitro et à l'aide de xénogreffes de neuroblastome, cette étude met en évidence des mécanismes par lesquels le gène GRHL1 joue un rôle de suppresseur de tumeurs

GRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3

Fabian, Johannes ; Lodrini, Marco ; Oehme, Ina ; Schier, Marie C. ; Thole, Theresa M. ; Hielscher, Thomas ; Kopp-Schneider, Annette ; Opitz, Lennart ; Capper, David ; von Deimling, Andreas ; Wiegand, Inga ; Milde, Till ; Mahlknecht, Ulrich ; Westermann, Frank ; Popanda, Odilia ; Roels, Frederik ; Hero, Barbara ; Berthold, Frank ; Fischer, Matthias ; Kulozik, Andreas ; Witt, Olaf ; Deubzer, Hedwig E.

Neuroblastoma is an embryonic solid tumor of neural crest origin and accounts for 11% of all cancer-related deaths in children. Novel therapeutic strategies are therefore urgently required. MYCN oncogene amplification, which occurs in 20% of neuroblastomas, is a hallmark of high risk. Here we aimed to exploit molecular mechanisms that can be pharmacologically addressed with epigenetically modifying drugs, such as HDAC inhibitors. GRHL1, a gene critical for Drosophila neural development, [...]

Menée à partir d'échantillons tumoraux prélevés sur 133 patients chinois atteints d'un cancer du poumon non à petites cellules, puis in vitro, cette étude met en évidence des mécanismes par lesquels la protéine RNF146 favorise le développement et la progression de la maladie

Overexpression of RNF146 in Non-Small Cell Lung Cancer Enhances Proliferation and Invasion of Tumors through the Wnt/β-catenin Signaling Pathway

Gao, Ying ; Song, Chengyang ; Hui, Linping ; Li, Chun-yu ; Wang, Junying ; Tian, Ye ; Han, Xu ; Chen, Yong ; Tian, Da-Li ; Qiu, Xueshan ; Wang, Enhua

Studies have suggested a possible correlation between the newly identified E3 ubiquitin ligase ring finger protein 146 (RNF146) and tumor development. However, until now, studies on RNF146 have been restricted to poly(ADP-ribosyl)ation and ubiquitin ligation, whereas the role of RNF146 in tumor biology has rarely been reported. In the present study, the role of RNF146 in non-small cell lung cancer (NSCLC) was investigated. The results showed that the expression of RNF146 was increased in [...]

Menée in vitro, in vivo et à partir de données d'analyse d'échantillons de tumeurs métastatiques prélevés sur des patients atteints d'un cancer de la prostate, cette étude met en évidence le rôle joué par la kinase GRK3 dans la progression et le processus métastatique de la maladie

GRK3 is essential for metastatic cells and promotes prostate tumor progression

Li, Wenliang ; Ai, Nanping ; Wang, Suming ; Bhattacharya, Nandita ; Vrbanac, Vladimir ; Collins, Michael ; Signoretti, Sabina ; Hu, Yanhui ; Boyce, Frederick M. ; Gravdal, Karsten ; Halvorsen, Ole J. ; Nalwoga, Hawa ; Akslen, Lars A. ; Harlow, Ed ; Watnick, Randolph S.

The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein–coupled receptor kinase 3 (GRK3; or β-adrenergic receptor kinase 2) was not only [...]