Menée sur 28 échantillons tumoraux prélevés sur des patients atteints d'un cholangiocarcinome intrahépatique, cette étude identifie des anomalies génomiques susceptibles d'être associées à une thérapie ciblée

New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing

Ross, Jeffrey S. ; Wang, Kai ; Gay, Laurie ; Al-Rohil, Rami ; Rand, Janne V. ; Jones, David M. ; Lee, Hwa J. ; Sheehan, Christine E. ; Otto, Geoff A. ; Palmer, Gary ; Yelensky, Roman ; Lipson, Doron ; Morosini, Deborah ; Hawryluk, Matthew ; Catenacci, Daniel V. T. ; Miller, Vincent A. ; Churi, Chaitanya ; Ali, Siraj ; Stephens, Philip J.

Background. Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized [...]

Menée sur des lignées cellulaires cancéreuses, cette étude met en évidence le rôle joué par l'expression du gène ARID1B dans la prolifération des cellules présentant une mutation du gène ARID1A

ARID1B is a specific vulnerability in ARID1A-mutant cancers

Helming, Katherine C. ; Wang, Xiaofeng ; Wilson, Boris G. ; Vazquez, Francisca ; Haswell, Jeffrey R. ; Manchester, Haley E. ; Kim, Youngha ; Kryukov, Gregory V. ; Ghandi, Mahmoud ; Aguirre, Andrew J. ; Jagani, Zainab ; Wang, Zhong ; Garraway, Levi A. ; Hahn, William C. ; Roberts, Charles W. M.

Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene [...]

Menée sur des lignées cellulaires de cancer ovarien, cette étude identifie la présence fréquente de translocations entre les régions chromosomiques 11q13.2 et 19p13.2

Frequent translocations of 11q13.2 and 19p13.2 in ovarian cancer

Wang, Liang ; Wenners, Antonia ; Hilpert, Felix ; Fredrik, Regina ; Micci, Francesca ; Onkes, Wiebke ; Caliebe, Amke ; Maass, Nicolai ; Weimer, Jörg ; Arnold, Norbert

Aberrations of chromosome arm 19p in ovarian cancer were first described decades ago and have been confirmed in recent publications, which have focused on chromosome 11 as a translocation partner. Recently, genetic analysis of the ovarian cancer cell line SKOV3 revealed a rearrangement described as der(19)t(11;19)(q13.2;p13.2), which lead to a fusion protein containing parts of HOOK2 and frame shifted ACTN3 that had unknown functionality. To evaluate the frequency of these breakpoints, we used [...]

Menée sur une patiente atteinte d'un adénocarcinome avancé du poumon traité à l'aide de sorafenib et en rémission radiographique pendant 5 ans, puis sur une cohorte indépendante de patients, cette étude suggère que des mutations du gène ARAF sont associées à la réponse thérapeutique

Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma

Imielinski, Marcin ; Greulich, Heidi ; Kaplan, Bethany ; Araujo, Luiz ; Amann, Joseph ; Horn, Leora ; Schiller, Joan ; Villalona-Calero, Miguel A. ; Meyerson, Matthew ; Carbone, David P.

Targeted cancer therapies often induce “outlier” responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting [...]

Menée in silico et à l'aide de xénogreffes, cette étude identifie, dans le quatrième intron du gène FHIT, un micro-ARN impliqué dans la fonction de suppresseur de tumeurs attribuée à ce gène

Identification of a Tumor Suppressive Human Specific MicroRNA within the FHIT Tumor Suppressor Gene

Hu, Baocheng ; Ying, Xiaomin ; Wang, Jian ; Piriyapongsa, Jittima ; Jordan, I. King ; Sheng, Jipo ; Yu, Fang ; Zhao, Po ; Li, Yazhuo ; Wang, Hongyan ; Ng, Wooi Loon ; Hu, Shuofeng ; Wang, Xiang ; Wang, Chenguang ; Zheng, Xiaofei ; Li, Wuju ; Curran, Walter J. ; Wang, Ya

Loss or attenuated expression of the tumor suppressor gene FHIT is associated paradoxically with poor progression of human tumors. Fhit promotes apoptosis and regulates reactive oxygen species, however, the mechanism by which Fhit inhibits tumor growth in animals remains unclear. In this study, we used a multi-discliplinary approach based on bioinformatics, small RNA library screening, human tissue analysis and a xenograft mouse model to identify a novel member of the miR-548 family in the [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la perte du gène Brg1, une sous-unité d'un complexe de remodelage de la chromatine, dans le développement d'un adénocarcinome canalaire du pancréas

The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma

von Figura, Guido ; Fukuda, Akihisa ; Roy, Nilotpal ; Liku, Muluye E. ; Morris Iv, John P. ; Kim, Grace E. ; Russ, Holger A. ; Firpo, Matthew A. ; Mulvihill, Sean J. ; Dawson, David W. ; Ferrer, Jorge ; Mueller, William F. ; Busch, Anke ; Hertel, Klemens J. ; Hebrok, Matthias

Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN–PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'œstradiol régule la survie des cellules mammaires présentant des mutations du gène suppresseur de tumeur BRCA1, ce qui permet de rendre compte de l'effet d'une ovariectomie sur le risque de cancer du sein ou d'une récidive chez les femmes porteuses de mutations BRCA1

Estrogen controls the survival of BRCA1-deficient cells via a PI3K–NRF2-regulated pathway

Gorrini, Chiara ; Gang, Bevan P. ; Bassi, Christian ; Wakeham, Andrew ; Baniasadi, Shakiba Pegah ; Hao, Zhenyue ; Li, Wanda Y. ; Cescon, David W. ; Li, Yen-Ting ; Molyneux, Sam ; Penrod, Nadia ; Lupien, Mathieu ; Schmidt, Edward E. ; Stambolic, Vuk ; Gauthier, Mona L. ; Mak, Tak W.

Mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. The mechanism underlying the tissue-specific nature of BRCA1’s tumor suppression is obscure. We previously showed that the antioxidant pathway regulated by the transcription factor NRF2 is defective in BRCA1-deficient cells. Reactivation of NRF2 through silencing of its negative regulator KEAP1 permitted the survival of BRCA1-null cells. Here we show that estrogen (E2) increases the expression of [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, dans le micro-environnement d'une tumeur mammaire, les voies de signalisation STAT3 et

Tumor-Induced STAT3 Signaling in Myeloid Cells Impairs Dendritic Cell Generation by Decreasing

Farren, Matthew R. ; Carlson, Louise M. ; Netherby, Colleen S. ; Lindner, Inna ; Li, Pui-Kai ; Gabrilovich, Dmitry I. ; Abrams, Scott I. ; Lee, Kelvin P.

A major mechanism by which cancers escape control by the immune system is by blocking the differentiation of myeloid cells into dendritic cells (DCs), immunostimulatory cells that activate antitumor T cells. Tumor-dependent activation of signal transducer and activator of transcription 3 (STAT3) signaling in myeloid progenitor cells is thought to cause this block in their differentiation. In addition, a signaling pathway through protein kinase C

Cet article passe en revue les travaux récents sur le rôle des micro-ARNs dans le processus métastatique

Regulation of microRNAs in Cancer Metastasis

Bouyssou, Juliette M. C. ; Manier, Salomon ; Huynh, Daisy ; Issa, Samar ; Roccaro, Aldo M. ; Ghobrial, Irene M.

Metastasis is a phenomenon of crucial importance in defining prognosis in patients with cancer and is often responsible for cancer-related mortality. It is known that several steps are necessary for clonal cells to disseminate from their primary tumor site and colonize distant tissues, thus originating metastatic lesions. Therefore, investigating the molecular actors regulating this process may provide helpful insights in the development of efficient therapeutic responses. Recent evidences have [...]

Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence des mécanismes par lesquels le micro-ARN miR-146a régule la division symétrique des cellules souches de cancer colorectal et, ainsi, la transition épithélio-mésenchymateuse

MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells

Hwang, Wei-Lun ; Jiang, Jeng-Kae ; Yang, Shung-Haur ; Huang, Tse-Shun ; Lan, Hsin-Yi ; Teng, Hao-Wei ; Yang, Chih-Yung ; Tsai, Ya-Ping ; Lin, Chi-Hung ; Wang, Hsei-Wei ; Yang, Muh-Hwa

Asymmetrical cell division (ACD) maintains the proper number of stem cells to ensure self-renewal. In cancer cells, the deregulation of ACD disrupts the homeostasis of the stem cell pool and promotes tumour growth. However, this mechanism is unclear. Here, we show a reduction of ACD in spheroid-derived colorectal cancer stem cells (CRCSCs) compared with differentiated cancer cells. The epithelial–mesenchymal transition (EMT) inducer Snail is responsible for the ACD-to-symmetrical cell division [...]