Menée sur des fibroblastes prélevés sur 9 patients présentant une aneuploïdie constitutionnelle et 2 témoins, puis sur des lignées cellulaires de cancer colorectal, cette étude suggère que la présence d'un chromosome supplémentaire n'est pas une cause suffisante d'instabilité chromosomique caractéristique des cellules cancéreuses

Whole chromosome gain does not in itself confer cancer-like chromosomal instability

Valind, Anders ; Jin, Yuesheng ; Baldetorp, Bo ; Gisselsson, David

Constitutional aneuploidy is typically caused by a single-event meiotic or early mitotic error. In contrast, somatic aneuploidy, found mainly in neoplastic tissue, is attributed to continuous chromosomal instability. More debated as a cause of aneuploidy is aneuploidy itself; that is, whether aneuploidy per se causes chromosomal instability, for example, in patients with inborn aneuploidy. We have addressed this issue by quantifying the level of somatic mosaicism, a proxy marker of chromosomal [...]

Menée initialement sur un patient présentant une mutation germinale du gène SAMHD1 et ayant développé une leucémie lymphocytaire chronique à l'âge de 24 ans, puis sur des échantillons prélevés dans le cadre d'un essai clinique, cette étude met en évidence le rôle joué par des mutations de SAMHD1 dans le développement de la maladie

SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage

Clifford, Ruth ; Louis, Tania ; Robbe, Pauline ; Ackroyd, Sam ; Burns, Adam ; Timbs, Adele T. ; Colopy, Glen W. ; Dreau, Helene ; Sigaux, Francois ; Judde, Jean Gabriel ; Rotger, Margalida ; Telenti, Amalio ; Lin, Yea-Lih ; Pasero, Philippe ; Maelfait, Jonathan ; Titsias, Michalis ; Cohen, Dena R. ; Henderson, Shirley J. ; Ross, Mark ; Bentley, David ; Hillmen, Peter ; Pettitt, Andrew ; Rehwinkel, Jan ; Knight, Samantha J.L. ; Taylor, Jenny C. ; Crow, Yanick J. ; Benkirane, Monsef ; Schuh, Anna

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTP TPH) and a nuclease that restricts HIV-1 in non-cycling cells. Germline mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal WGS study of chronic lymphocytic leukemia (CLL) we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germline SAMHD1 mutation who developed CLL at [...]

Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un mélanome (233 tumeurs primitives, 77 métastases), cette étude identifie diverses mutations du gène PP6C associées à différentes évolutions de la maladie et, pour certaines d'entre elles, à la réponse thérapeutique aux inhibiteurs de la kinase Aurora A

PP6C Hotspot Mutations in Melanoma Display Sensitivity to Aurora Kinase Inhibition

Gold, Heidi L. ; Wengrod, Jordan ; Vaega-Saenz de Miera, Eleazar ; Wang, Ding ; Fleming, Nathaniel ; Sikkema, Lisa ; Kirchoff, Tomas ; Hochman, Tsivia ; Goldberg, Judith D. ; Osman, Iman ; Gardner, Lawrence B.

Recent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from melanoma patients (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in both primary and metastatic melanoma patients. Despite [...]

Menée sur des échantillons de tumeurs primitives et récidivantes prélevés sur 23 patients atteints d'un gliome, cette étude de séquençage de l'exome met en évidence l'absence fréquente, dans les tumeurs récidivantes, de mutations de plusieurs gènes, notamment TP53, ATRX, SMARCA4 et BRAF, détectées dans les tumeurs primitives

Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma

Johnson, Brett E. ; Mazor, Tali ; Hong, Chibo ; Barnes, Michael ; Aihara, Koki ; McLean, Cory Y. ; Fouse, Shaun D. ; Yamamoto, Shogo ; Ueda, Hiroki ; Tatsuno, Kenji ; Asthana, Saurabh ; Jalbert, Llewellyn E. ; Nelson, Sarah J. ; Bollen, Andrew W. ; Gustafson, W. Clay ; Charron, Elise ; Weiss, William A. ; Smirnov, Ivan V. ; Song, Jun S. ; Olshen, Adam B. ; Cha, Soonmee ; Zhao, Yongjun ; Moore, Richard A. ; Mungall, Andrew J. ; Jones, Steven J. M. ; Hirst, Martin ; Marra, Marco A. ; Saito, Nobuhito ; Aburatani, Hiroyuki ; Mukasa, Akitake ; Berger, Mitchel S. ; Chang, Susan M. ; Taylor, Barry S. ; Costello, Joseph F.

Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du gène AKT2, le micro-ARN miR-302b joue un rôle de suppresseur de tumeurs dans les carcinomes hépatocellulaires

miRNA-302b Suppresses Human Hepatocellular Carcinoma by Targeting AKT2

Wang, Lumin ; Yao, Jiayi ; Zhang, Xiaogang ; Guo, Bo ; Le, Xiaofeng ; Cubberly, Mark ; Li, Zongfang ; Nan, Kejun ; Song, Tusheng ; Huang, Chen

miRNAs (miRs) play a critical role in human cancers including hepatocellular carcinoma (HCC). Although miR-302b has been suggested to function as a tumor repressor in other cancers, its role in HCC is unknown. This study investigated the expression and functional role of miR-302b in human HCC. The expression level of miR-302b is dramatically decreased in clinical HCC specimens, as compared to their respective non-neoplastic counterparts, and in HCC cell lines. Overexpression of miR-302b [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en plus d'une perte de sa fonction de suppresseur de tumeur, certaines mutations du gène p53 lui procurent une fonction d'oncogène en stimulant l'effet Warburg

Tumour-associated mutant p53 drives the Warburg effect

Zhang, Cen ; Liu, Juan ; Liang, Yingjian ; Wu, Rui ; Zhao, Yuhan ; Hong, Xuehui ; Lin, Meihua ; Yu, Haiyang ; Liu, Lianxin ; Levine, Arnold J. ; Hu, Wenwei ; Feng, Zhaohui

Tumour cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Its mechanism is not well understood. The tumour suppressor gene p53 is frequently mutated in tumours. Many tumour-associated mutant p53 (mutp53) proteins not only lose tumour suppressive function but also gain new oncogenic functions that are independent of wild-type p53, defined as mutp53 gain of function (GOF). Here we show that tumour-associated mutp53 stimulates the Warburg [...]

Menée sur des modèles murins et des échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde, cette étude met en évidence des mécanismes par lesquels, en entretenant un état de quiescence, la protéine Pten joue un rôle de suppresseur de tumeurs dans les cellules souches des follicules pileux

Stem cell quiescence acts as a tumour suppressor in squamous tumours

White, A. C. ; Khuu, J. K. ; Dang, C. Y. ; Hu, J. ; Tran, K. V. ; Liu, A. ; Gomez, S. ; Zhang, Z. ; Yi, R. ; Scumpia, P. ; Grigorian, M. ; Lowry, W. E.

In some organs, adult stem cells are uniquely poised to serve as cancer cells of origin. It is unclear, however, whether tumorigenesis is influenced by the activation state of the adult stem cell. Hair follicle stem cells (HFSCs) act as cancer cells of origin for cutaneous squamous cell carcinoma and undergo defined cycles of quiescence and activation. The data presented here show that HFSCs are unable to initiate tumours during the quiescent phase of the hair cycle, indicating that the [...]

Cet article passe en revue les travaux récents sur le rôle des anomalies du mécanisme d'épissage alternatif dans les cancers

Hallmarks of alternative splicing in cancer

Oltean, S. ; Bates, D. O.

The immense majority of genes are alternatively spliced and there are many isoforms specifically associated with cancer progression and metastasis. The splicing pattern of specific isoforms of numerous genes is altered as cells move through the oncogenic process of gaining proliferative capacity, acquiring angiogenic, invasive, antiapoptotic and survival properties, becoming free from growth factor dependence and growth suppression, altering their metabolism to cope with hypoxia, enabling them [...]

Cet article passe en revue les travaux récents sur le profil immunologique des cellules souches cancéreuses dans les tumeurs solides

Immunology of cancer stem cells in solid tumours. A review

Maccalli, Cristina ; Volontè, Andrea ; Cimminiello, Carolina ; Parmiani, Giorgio

Cancer stem cells (CSCs) represent a minor subpopulation of tumour cells that share some features with the normal stem cells of the tissue from which tumour derives and have the properties of self-renewal, multiple differentiation and tumour initiation (tumour-initiating cells, TICs). Thus CSCs/TICs need to survive cancer therapies in order to provide new, more differentiated, metastatic-prone tumour cells. This occurs through different signals delivered within the tumour microenvironment. The [...]

Cet article passe en revue les travaux récents sur le rôle de la protéine kinase C dans la tumorigénèse et le processus métastatique

Protein kinase C and cancer: what we know and what we do not

Garg, R. ; Benedetti, L. G. ; Abera, M. B. ; Wang, H. ; Abba, M. ; Kazanietz, M. G.

Since their discovery in the late 1970s, protein kinase C (PKC) isozymes represent one of the most extensively studied signaling kinases. PKCs signal through multiple pathways and control the expression of genes relevant for cell cycle progression, tumorigenesis and metastatic dissemination. Despite the vast amount of information concerning the mechanisms that control PKC activation and function in cellular models, the relevance of individual PKC isozymes in the progression of human cancer is [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par le gène Cnot2 dans le processus métastatique

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

Faraji, Farhoud ; Hu, Ying ; Wu, Gang ; Goldberger, Natalie E. ; Walker, Renard C. ; Zhang, Jinghui ; Hunter, Kent W.

Metastasis is the result of stochastic genomic and epigenetic events leading to gene expression profiles that drive tumor dissemination. Here we exploit the principle that metastatic propensity is modified by the genetic background to generate prognostic gene expression signatures that illuminate regulators of metastasis. We also identify multiple microRNAs whose germline variation is causally linked to tumor progression and metastasis. We employ network analysis of global gene expression [...]

Menée sur des cultures cellulaires dérivées d'une tumeur de carcinome ovarien à cellules claires, cette étude met en évidence une importante hétérogénéité intratumorale des populations de cellules souches cancéreuses

Niche-Dependent Gene Expression Profile of Intratumoral Heterogeneous Ovarian Cancer Stem Cell Populations

Abelson, Sagi ; Shamai, Yeela ; Berger, Liron ; Skorecki, Karl ; Tzukerman, Maty

Intratumoral heterogeneity challenges existing paradigms for anti-cancer therapy. We have previously demonstrated that the human embryonic stem cells (hESC)-derived cellular microenvironment in immunocompromised mice, enables functional distinction of heterogeneous tumor cells, including cells which do not grow into a tumor in a conventional direct tumor xenograft platform. We have identified and characterized six cancer cell subpopulations each clonally expanded from a single cell, derived [...]

Menée sur 40 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un carcinome de la prostate à divers stades de la maladie, cette étude met en évidence des anomalies d'expression de plusieurs micro-ARNs

Comparative microRNA profiling of prostate carcinomas with increasing tumor stage by deep-sequencing

Hart, Martin ; Nolte, Elke ; Wach, Sven ; Szczyrba, Jaroslaw ; Taubert, Helge ; Rau, Tilman ; Hartmann, Arndt ; Grässer, Friedrich A. ; Wullich, Bernd

MicroRNAs (miRNAs) post-transcriptionally regulate gene expression and are important in tumorigenesis. Previous deep-sequencing identified the miRNA profile of prostate carcinoma (PCa) vs. non-malignant prostate tissue. Here, we generated by deep sequencing miRNA expression profiles of PCa with increasing tumor stage relative to corresponding non-malignant and healthy prostate tissue and detected clearly changed miRNA expression patterns. The miRNA profiles of the healthy and non-malignant [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en maintenant les cellules tumorales dans un état indifférencié, le facteur TNF-alpha favorise la progression d'un ostéosarcome

TNF[alpha] promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

Mori, T. ; Sato, Y. ; Miyamoto, K. ; Kobayashi, T. ; Shimizu, T. ; Kanagawa, H. ; Katsuyama, E. ; Fujie, A. ; Hao, W. ; Tando, T. ; Iwasaki, R. ; Kawana, H. ; Morioka, H. ; Matsumoto, M. ; Saya, H. ; Toyama, Y. ; Miyamoto, T.

Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNF[alpha] is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, indépendamment d'anomalies génomiques, une hypoxie du microenvironnement tumoral est susceptible d'activer une voie de signalisation (RhoA-ROCK1) favorisant la progression d'un cancer du sein

Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells

Gilkes, Daniele M. ; Xiang, Lisha ; Lee, Sun Joo ; Chaturvedi, Pallavi ; Hubbi, Maimon E. ; Wirtz, Denis ; Semenza, Gregg L.

Overexpression of Rho kinase 1 (ROCK1) and the G protein RhoA is implicated in breast cancer progression, but oncogenic mutations are rare, and the molecular mechanisms that underlie increased ROCK1 and RhoA expression have not been determined. RhoA-bound ROCK1 phosphorylates myosin light chain (MLC), which is required for actin-myosin contractility. RhoA also activates focal adhesion kinase (FAK) signaling. Together, these pathways are critical determinants of the motile and invasive phenotype [...]

Menée in vitro à l'aide d'un modèle tri-dimensionnel, cette étude met en évidence la spécialisation de certaines populations cellulaires tumorales dans le processus invasif d'un cancer du sein

Collective Invasion in Breast Cancer Requires a Conserved Basal Epithelial Program

Cheung, Kevin J ; Gabrielson, Edward ; Werb, Zena ; Ewald, Andrew J

Carcinomas typically invade as a cohesive multicellular unit, a process termed collective invasion. It remains unclear how different subpopulations of cancer cells contribute to this process. We developed three-dimensional (3D) organoid assays to identify the most invasive cancer cells in primary breast tumors. Collective invasion was led by specialized cancer cells that were defined by their expression of basal epithelial genes, such as cytokeratin-14 (K14) and p63. Furthermore, K14+ cells led [...]