A partir d'échantillons tumoraux prélevés sur 1 454 patients atteints d'une tumeur solide (15 types de cancer), cette étude japonaise identifie un ensemble d'oncogènes dont la surexpression est associée à des anomalies du nombre de copies

Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors

Ohshima, Keiichi ; Hatakeyama, Keiichi ; Nagashima, Takeshi ; Watanabe, Yuko ; Kanto, Kaori ; Doi, Yuki ; Ide, Tomomi ; Shimoda, Yuji ; Tanabe, Tomoe ; Ohnami, Sumiko ; Ohnami, Shumpei ; Serizawa, Masakuni ; Maruyama, Koji ; Akiyama, Yasuto ; Urakami, Kenichi ; Kusuhara, Masatoshi ; Mochizuki, Tohru ; Yamaguchi, Ken

Identification of driver genes contributes to the understanding of cancer etiology and is imperative for the development of individualized therapies. Gene amplification is a major event in oncogenesis. Driver genes with tumor-specific amplification-dependent overexpression can be therapeutic targets. In this study, we aimed to identify amplification-dependent driver genes in 1,454 solid tumors, across more than 15 cancer types, by integrative analysis of gene expression and copy number. [...]

A l'aide d'échantillons sanguins prélevés sur 369 patients pédiatriques atteints d'une leucémie myéloïde aiguë, cette étude japonaise identifie des mutations des gènes ASXL1 ou ASXL2 chez les patients présentant une translocation t(8;21)(q22;q22)

ASXL2 mutations are frequently found in pediatric AML patients with t(8;21)/ RUNX1-RUNX1T1 and associated with a better prognosis

Yamato, Genki ; Shiba, Norio ; Yoshida, Kenichi ; Shiraishi, Yuichi ; Hara, Yusuke ; Ohki, Kentaro ; Okubo, Jun ; Okuno, Haruna ; Chiba, Kenichi ; Tanaka, Hiroko ; Kinoshita, Akitoshi ; Moritake, Hiroshi ; Kiyokawa, Nobutaka ; Tomizawa, Daisuke ; Park, Myoung-ja ; Sotomatsu, Manabu ; Taga, Takashi ; Adachi, Souichi ; Tawa, Akio ; Horibe, Keizo ; Arakawa, Hirokazu ; Miyano, Satoru ; Ogawa, Seishi ; Hayashi, Yasuhide

ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 [...]

A partir de données du projet "The Cancer Genome Atlas" portant sur des échantillons d'adénocarcinomes du rectum ou du côlon, cette étude identifie la présence, dans le génome nucléaire, d'ADN mitochondrial présentant des anomalies du nombre de copies

Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma

Srinivasainagendra, Vinodh ; Sandel, Michael W. ; Singh, Bhupendra ; Sundaresan, Aishwarya ; Mooga, Ved P. ; Bajpai, Prachi ; Tiwari, Hemant K. ; Singh, Keshav K.

Colorectal adenocarcinomas are characterized by abnormal mitochondrial DNA (mtDNA) copy number and genomic instability, but a molecular interaction between mitochondrial and nuclear genome remains unknown. Here we report the discovery of increased copies of nuclear mtDNA (NUMT) in colorectal adenocarcinomas, which supports link between mtDNA and genomic instability in the nucleus. We name this phenomenon of nuclear occurrence of mitochondrial component as numtogenesis. We provide a description [...]

A partir d'échantillons tumoraux prélevés sur 9 patients atteints d'un médulloblastome, 16 atteints d'un gliome de haut grade et 10 atteints d'un carcinome à cellules rénales, cette étude met notamment en évidence une importante hétérogénéité spatiale dans les tumeurs de médulloblastome

Spatial heterogeneity in medulloblastoma

Morrissy, A. Sorana ; Cavalli, Florence M. G. ; Remke, Marc ; Ramaswamy, Vijay ; Shih, David J. H. ; Holgado, Borja L. ; Farooq, Hamza ; Donovan, Laura K. ; Garzia, Livia ; Agnihotri, Sameer ; Kiehna, Erin N. ; Mercier, Eloi ; Mayoh, Chelsea ; Papillon-Cavanagh, Simon ; Nikbakht, Hamid ; Gayden, Tenzin ; Torchia, Jonathon ; Picard, Daniel ; Merino, Diana M. ; Vladoiu, Maria ; Luu, Betty ; Wu, Xiaochong ; Daniels, Craig ; Horswell, Stuart ; Thompson, Yuan Yao ; Hovestadt, Volker ; Northcott, Paul A. ; Jones, David T. W. ; Peacock, John ; Wang, Xin ; Mack, Stephen C. ; Reimand, Jüri ; Albrecht, Steffen ; Fontebasso, Adam M. ; Thiessen, Nina ; Li, Yisu ; Schein, Jacqueline E. ; Lee, Darlene ; Carlsen, Rebecca ; Mayo, Michael ; Tse, Kane ; Tam, Angela ; Dhalla, Noreen ; Ally, Adrian ; Chuah, Eric ; Cheng, Young ; Plettner, Patrick ; Li, Haiyan I. ; Corbett, Richard D. ; Wong, Tina ; Long, William ; Loukides, James ; Buczkowicz, Pawel ; Hawkins, Cynthia E. ; Tabori, Uri ; Rood, Brian R. ; Myseros, John S. ; Packer, Roger J. ; Korshunov, Andrey ; Lichter, Peter ; Kool, Marcel ; Pfister, Stefan M. ; Schüller, Ulrich ; Dirks, Peter ; Huang, Annie ; Bouffet, Eric ; Rutka, James T. ; Bader, Gary D. ; Swanton, Charles ; Ma, Yusanne ; Moore, Richard A. ; Mungall, Andrew J. ; Majewski, Jacek ; Jones, Steven J. M. ; Das, Sunit ; Malkin, David ; Jabado, Nada ; Marra, Marco A. ; Taylor, Michael D.

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous [...]

A partir d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire, puis menée sur des modèles murins, cette étude met en évidence le rôle joué par des cellules étoilées hépatiques dans la progression tumorale

Hepatic stellate cells limit hepatocellular carcinoma progression through the orphan receptor endosialin

Mogler, Carolin ; König, Courtney ; Wieland, Matthias ; Runge, Anja ; Besemfelder, Eva ; Komljenovic, Dorde ; Longerich, Thomas ; Schirmacher, Peter ; Augustin, Hellmut G.

Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. A major contributor to HCC progression is the cross talk between tumor cells and the surrounding stroma including activated hepatic stellate cells (HSC). Activation of HSC during liver damage leads to upregulation of the orphan receptor endosialin (CD248), which contributes to regulating the balance of liver regeneration and fibrosis. Based on the established role of endosialin in regulating HSC/hepatocyte [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en favorisant la dégradation de protéines mal repliées, les protéines TRIM exercent un rôle dans la transformation maligne

Enhanced Degradation of Misfolded Proteins Promotes Tumorigenesis

Chen, Liang ; Brewer, Michael D. ; Guo, Lili ; Wang, Ruoxing ; Jiang, Peng ; Yang, Xiaolu

An adequate cellular capacity to degrade misfolded proteins is critical for cell survival and organismal health. A diminished capacity is associated with aging and neurodegenerative diseases; however, the consequences of an enhanced capacity remain undefined. Here, we report that the ability to clear misfolded proteins is increased during oncogenic transformation and is reduced upon tumor cell differentiation. The augmented capacity mitigates oxidative stress associated with oncogenic growth [...]

Menée sur un grand nombre de lignées cellulaires cancéreuses, cette étude met en évidence le rôle joué par une oxydoréductase (2-oxoglutarate déshydrogénase) dans la prolifération des cellules cancéreuses présentant des mutations du gène PIK3CA

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Ilic, Nina ; Birsoy, Kivanc ; Aguirre, Andrew J. ; Kory, Nora ; Pacold, Michael E. ; Singh, Shambhavi ; Moody, Susan E. ; DeAngelo, Joseph D. ; Spardy, Nicole A. ; Freinkman, Elizaveta ; Weir, Barbara A. ; Tsherniak, Aviad ; Cowley, Glenn S. ; Root, David E. ; Asara, John M. ; Vazquez, Francisca ; Widlund, Hans R. ; Sabatini, David M. ; Hahn, William C.

Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en ciblant la famille des protéines BCl-2, le complexe protéique p53/p21 régule le processus invasif et l'apoptose

The p53/p21 complex regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins

Kim, Eun Mi ; Jung, Chan-Hun ; Kim, Jongdoo ; Hwang, Sang-Gu ; Park, JongKuk ; Um, Hong-Duck

The tumor suppressor p53 binds pro-survival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts pro-apoptotic or anti-invasive functions depending on stress context. Based on our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a [...]

Menée in vitro et in vivo sur des modèles de néoplasies intraépithéliales du pancréas, cette étude met en évidence des mécanismes par lesquels des cellules nerveuses du micro-environnement tumoral favorisent la croissance tumorale

PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk

Sinha, Smrita ; Fu, Ya-Yuan ; Grimont, Adrien ; Ketcham, Maren ; Lafaro, Kelly ; Saglimbeni, Joseph A. ; Askan, Gokce ; Bailey, Jennifer M. ; Melchor, Jerry P. ; Zhong, Yi ; Joo, Min Geol ; Grbovic-Huezo, Olivera ; Yang, In-Hong ; Basturk, Olca ; Baker, Lindsey ; Park, Young ; Kurtz, Robert C. ; Tuveson, David ; Leach, Steven D. ; Pasricha, Pankaj J.

Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here, we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor neurokinin 1-R (NK1-R). Using organoid [...]

Menée à l'aide de lignées cellulaires d'adénocarcinome canalaire du pancréas et de cultures tri-dimensionnelles, cette étude met en évidence des mécanismes par lesquels, en augmentant l'expression des facteurs de transcription YAP1 et TAZ, la signalisation eIF5A-PEAK1 favorise la croissance tumorale

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

Strnadel, Jan ; Choi, Sunkyu ; Fujimura, Ken ; Wang, Huawei ; Zhang, Wei ; Wyse, Meghan ; Wright, Tracy ; Gross, Emilie ; Peinado, Carlos ; Park, Hyun Woo ; Bui, Jack ; Kelber, Jonathan ; Bouvet, Michael ; Guan, Kun-Liang ; Klemke, Richard L.

In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we [...]

Cette étude passe en revue le rôle des mutations du gène APC impliquées dans le développement et la progression d'une tumeur colorectale

Multiple Roles of APC and its Therapeutic Implications in Colorectal Cancer

Zhang, Lu ; Shay, Jerry W.

Adenomatous polyposis coli (APC) is widely accepted as a tumor suppressor gene highly mutated in colorectal cancers (CRC). Mutation and inactivation of this gene is a key and early event almost uniquely observed in colorectal tumorigenesis. Alterations in the APC gene generate truncated gene products, leading to activation of the Wnt signaling pathway and deregulation of multiple other cellular processes. It has been a mystery why most patients with CRC retain a truncated APC protein, but [...]

Menée sur des lignées cellulaires de carcinomes du sein et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par une surexpression de l'oncogène EVI1 spécifiquement dans les carcinomes triplement négatifs, à la différence des carcinomes HER2+

Prominent Oncogenic Roles of EVI1 in Breast Carcinoma

Wang, Hui ; Schaefer, Thorsten ; Konantz, Martina ; Braun, Martin ; Varga, Zsuzsanna ; Paczulla, Anna M. ; Reich, Selina ; Jacob, Francis ; Perner, Sven ; Moch, Holger ; Fehm, Tanja N. ; Kanz, Lothar ; Schulze-Osthoff, Klaus ; Lengerke, Claudia

Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma where its contributions are unexplored. Analyzing a tissue microarray of 608 breast carcinoma patient specimens, we documented EVI1 overexpression in both estrogen receptor–positive (ER+) and estrogen receptor–negative (ER−) breast carcinomas. Here, we report prognostic relevance of EVI1 overexpression in triple-negative breast carcinoma but not in the [...]

Cet article passe en revue les travaux récents sur le rôle de la signalisation du calcium dans la prolifération des cellules cancéreuses, le processus invasif et la résistance thérapeutique

The calcium-cancer signalling nexus

Monteith, Gregory R. ; Prevarskaya, Natalia ; Roberts-Thomson, Sarah J.

The calcium signal is a powerful and multifaceted tool by which cells can achieve specific outcomes. Cellular machinery important in tumour progression is often driven or influenced by changes in calcium ions; in some cases this regulation occurs within spatially defined regions. Over the past decade there has been a deeper understanding of how calcium signalling is remodelled in some cancers and the consequences of calcium signalling on key events such as proliferation, invasion and [...]

Menée in vitro et in vivo sur des modèles de carcinome canalaire in situ du sein, cette étude met en évidence des mécanismes par lesquels la protéine SMARCE1 favorise les processus invasif et métastatique

SMARCE1 is required for the invasive progression of in situ cancers

Sokol, Ethan S. ; Feng, Yu-Xiong ; Jin, Dexter X. ; Tizabi, Minu D. ; Miller, Daniel H. ; Cohen, Malkiel A. ; Sanduja, Sandhya ; Reinhardt, Ferenc ; Pandey, Jai ; Superville, Daphne A. ; Jaenisch, Rudolf ; Gupta, Piyush B.

Advances in mammography have sparked an exponential increase in the detection of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). More than 50% of DCIS lesions are benign and will remain indolent, never progressing to invasive cancers. However, the factors that promote DCIS invasion remain poorly understood. Here, we show that SMARCE1 is required for the invasive progression of DCIS and other early-stage tumors. We show that SMARCE1 drives invasion by regulating the [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par des lymphocytes T auxiliaires dans la normalisation du réseau vasculaire tumoral

Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming

Tian, Lin ; Goldstein, Amit ; Wang, Hai ; Ching Lo, Hin ; Sun Kim, Ik ; Welte, Thomas ; Sheng, Kuanwei ; Dobrolecki, Lacey E. ; Zhang, Xiaomei ; Putluri, Nagireddy ; Phung, Thuy L. ; Mani, Sendurai A. ; Stossi, Fabio ; Sreekumar, Arun ; Mancini, Michael A. ; Decker, William K. ; Zong, Chenghang ; Lewis, Michael T. ; Zhang, Xiang H. F.

Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis. This paradox may be resolved by vessel normalization, which involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia. Although these processes alter tumour progression, their regulation is poorly understood. Here we show that type 1 T helper (TH1) cells play a crucial role in vessel normalization. Bioinformatic [...]