Menée à partir de données issues du projet "The Cancer Genome Atlas", puis sur des lignées cellulaires, cette étude montre que la surexpression d'une lysine déméthylase (KDM4A) favorise un gain du nombre de copies de gènes dans des régions génomiques spécifiques (1q12, 1q21 et Xq13.1) sans instabilité chromosomique globale

KDM4A Lysine Demethylase Induces Site-Specific Copy Gain and Rereplication of Regions Amplified in Tumors

Black, Joshua C ; Manning, Amity L ; Van Rechem, Capucine ; Kim, Jaegil ; Ladd, Brendon ; Cho, Juok ; Pineda, Cristiana M ; Murphy, Nancy ; Daniels, Danette L ; Montagna, Cristina ; Lewis, Peter W ; Glass, Kimberly ; Allis, C.  David ; Dyson, Nicholas J ; Getz, Gad ; Whetstine, Johnathan R

Acquired chromosomal instability and copy number alterations are hallmarks of cancer. Enzymes capable of promoting site-specific copy number changes have yet to be identified. Here, we demonstrate that H3K9/36me3 lysine demethylase KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase, and [...]

Cet article passe en revue les travaux récents en génomique et épigénomique des cancers du sein

Next Generation analysis of breast cancer genomes for precision medicine

Previati, Maurizio ; Manfrini, Marco ; Galasso, Marco ; Zerbinati, Carlotta ; Palatini, Jeff ; Gasparini, Pierluigi ; Volinia, Stefano

For many years breast cancer classification has been based on histology and immune-histochemistry. New techniques, more strictly related to cancer biology, partially succeeded in fractionating patients, correlated to survival and better predicted the patient response to therapy. Nowadays, great expectations arise from massive parallel or high throughput next generation sequencing. Cancer genomics has already revolutionized our knowledge of breast cancer molecular pathology, paving the way to [...]

Cet article passe en revue les travaux récents menés à l'aide de modèles murins et de lignées cellulaires sur des mécanismes impliquant le récepteur des androgènes dans divers types de cancers (prostate, vessie, rein, poumon, sein et foie)

Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver

Chang, C. ; Lee, S. O. ; Yeh, S. ; Chang, T. M.

The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation CCL4-STAT3, des macrophages sont susceptibles d'induire la formation de tumeurs de la prostate

Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling

Fang, Lei-Ya ; Izumi, Kouji ; Lai, Kuo-Pao ; Liang, Liang ; Li, Lei ; Miyamoto, Hiroshi ; Lin, Wen-Jye ; Chang, Chawnshang

Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent co-culturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis, and that induction involves the alteration of signaling of macrophage androgen receptor (AR)-inflammatory chemokine CCL4-STAT3 activation as well as epithelial-to-mesenchymal transition (EMT) [...]

Menée à l'aide d'un modèle murin de cancer du côlon, cette étude met en évidence des mécanismes par lesquels les récepteurs à activité tyrosine kinase Axl et Mer, identifiés pour leur rôle de proto-oncogènes, peuvent aussi exercer une fonction anti-inflammatoire

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

Bosurgi, Lidia ; Bernink, Jochem H. ; Delgado Cuevas, Victor ; Gagliani, Nicola ; Joannas, Leonel ; Schmid, Edward T. ; Booth, Carmen J. ; Ghosh, Sourav ; Rothlin, Carla V.

The receptor tyrosine kinases Axl and Mer, belonging to the Tyro3, Axl and Mer (TAM) receptor family, are expressed in a number of tumor cells and have well-characterized oncogenic roles. The therapeutic targeting of these kinases is considered an anticancer strategy, and various inhibitors are currently under development. At the same time, Axl and Mer are expressed in dendritic cells and macrophages and have an essential function in limiting inflammation. Inflammation is an enabling [...]

A partir d'une méta-analyse de données d'expression de gènes portant sur plus de 1 000 échantillons tumoraux, puis menée in vitro et in vivo, cette étude identifie le rôle joué par ELTD1, un récepteur couplé aux protéines G, dans l'angiogenèse tumorale

A Core Human Primary Tumor Angiogenesis Signature Identifies the Endothelial Orphan Receptor ELTD1 as a Key Regulator of Angiogenesis

Masiero, Massimo ; Simões, Filipa Costa ; Han, Hee Dong ; Snell, Cameron ; Peterkin, Tessa ; Bridges, Esther ; Mangala, Lingegowda S ; Wu, Sherry Yen-Yao ; Pradeep, Sunila ; Li, Demin ; Han, Cheng ; Dalton, Heather ; Lopez-Berestein, Gabriel ; Tuynman, Jurriaan B ; Mortensen, Neil ; Li, Ji-Liang ; Patient, Roger ; Sood, Anil K ; Banham, Alison H ; Harris, Adrian L ; Buffa, Francesca M

Limited clinical benefits derived from anti-VEGF therapy have driven the identification of new targets involved in tumor angiogenesis. Here, we report an integrative meta-analysis to define the transcriptional program underlying angiogenesis in human cancer. This approach identified ELTD1, an orphan G-protein-coupled receptor whose expression is induced by VEGF/bFGF and repressed by DLL4 signaling. Extensive analysis of multiple cancer types demonstrates significant upregulation of ELTD1 in [...]

Menée sur une lignée cellulaire de cancer du sein, cette étude met en évidence le rôle de l'enzyme AID dans le processus de transition épithélio-mésenchymateuse

Activation-induced cytidine deaminase (AID) is necessary for the epithelial–mesenchymal transition in mammary epithelial cells

Muñoz, Denise P. ; Lee, Elbert L. ; Takayama, Sachiko ; Coppé, Jean-Philippe ; Heo, Seok-Jin ; Boffelli, Dario ; Di Noia, Javier M. ; Martin, David I. K.

Activation-induced cytidine deaminase (AID), which functions in antibody diversification, is also expressed in a variety of germ and somatic cells. Evidence that AID promotes DNA demethylation in epigenetic reprogramming phenomena, and that it is induced by inflammatory signals, led us to investigate its role in the epithelial–mesenchymal transition (EMT), a critical process in normal morphogenesis and tumor metastasis. We find that expression of AID is induced by inflammatory signals that [...]

Menée à l'aide d'un modèle murin de mélanome, cette étude met en évidence des mécanismes par lesquels, en inhibant le recrutement et/ou la différenciation de monocytes inflammatoires dans la peau, des lymphocytes T régulateurs CD4+ favorisent la progression tumorale

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells

Pommier, Arnaud ; Audemard, Alexandra ; Durand, Aurélie ; Lengagne, Renée ; Delpoux, Arnaud ; Martin, Bruno ; Douguet, Laetitia ; Le Campion, Armelle ; Kato, Masashi ; Avril, Marie-Françoise ; Auffray, Cédric ; Lucas, Bruno ; Prévost-Blondel, Armelle

The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels des oesinophiles sont susceptibles de favoriser la prolifération de cellules de myélome multiple dans le plasma

Induction of Malignant Plasma Cell Proliferation by Eosinophils

Wong, Tina W. ; Kita, Hirohito ; Hanson, Curtis A. ; Walters, Denise K. ; Arendt, Bonnie K. ; Jelinek, Diane F.

The biology of the malignant plasma cells (PCs) in multiple myeloma (MM) is highly influenced by the bone marrow (BM) microenvironment in which they reside. More specifically, BM stromal cells (SCs) are known to interact with MM cells to promote MM cell survival and proliferation. By contrast, it is unclear if innate immune cells within this same space also actively participate in the pathology of MM. Our study shows for the first time that eosinophils (Eos) can contribute to the biology of MM [...]

Menée in vitro, in vivo et sur des échantillons tumoraux, cette étude met en évidence des mécanismes par lesquels la protéine se liant à l'interleukine 18, produite dans des cellules épithéliales de l'ovaire en réponse à des facteurs du micro-environnement, est susceptible d'inhiber l'activité de l'interleukine 18

The IL-18 antagonist IL-18 Binding Protein is produced in the human ovarian cancer microenvironment

Grazia, Carbotti ; Barisione, Gaia ; Orengo, Anna M. ; Brizzolara, Antonella ; Airoldi, Irma ; Bagnoli, Marina ; Pinciroli, Patrizia ; Mezzanzanica, Delia ; Centurioni, Maria G. ; Fabbi, Marina ; Ferrini, Silvano

Purpose:Interleukin (IL)-18 is an immune-enhancing cytokine, which induces Interferon (IFN)-γ production, Th1-responses and anti-tumor effects. In turn, IFN-γ stimulates IL-18 Binding Protein (BP) production, which blocks IL-18 activity. In view of the potential use of IL-18 in epithelial ovarian cancer (EOC) immunotherapy, here we studied IL-18BP expression and its regulation by cytokines in EOC cells in vitro and in vivo. Experimental Design:Expression and production of IL-18BP in EOC cell [...]

Menée à l'aide d'un modèle murin de cancer du pancréas, cette étude met en évidence le rôle joué par les protéines p53 et Tap63 dans le processus métastatique

Functions of TAp63 and p53 in restraining the development of metastatic cancer

Tan, E. H. ; Morton, J. P. ; Timpson, P. ; Tucci, P. ; Melino, G. ; Flores, E. R. ; Sansom, O. J. ; Vousden, K. H. ; Muller, P. A. J.

Many tumours harbour mutations in the p53 tumour-suppressor gene that result in the expression of a mutant p53 protein. This mutant p53 protein has, in most cases, lost wild-type transcriptional activity and can also acquire novel functions in promoting invasion and metastasis. One of the mechanisms underlying these novel functions involves the ability of the mutant p53 to interfere with other transcription factors, including the p53 family protein TAp63. To investigate whether simultaneous [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la kinase FER favorise le processus métastatique d'un cancer du sein

FER kinase promotes breast cancer metastasis by regulating [alpha]6- and [beta]1-integrin-dependent cell adhesion and anoikis resistance

Ivanova, I. A. ; Vermeulen, J. F. ; Ercan, C. ; Houthuijzen, J. M. ; Saig, F. A. ; Vlug, E. J. ; van der Wall, E. ; van Diest, P. J. ; Vooijs, M. ; Derksen, P. W. B.

Metastatic breast cancer cannot be treated successfully. Currently, the targeted therapies for metastatic disease are limited to human epidermal growth factor receptor 2 and hormone receptor antagonists. Understanding the mechanisms of breast cancer growth and metastasis is therefore crucial for the development of new intervention strategies. Here, we show that FER kinase (FER) controls migration and metastasis of invasive human breast cancer cell lines by regulating

Cet article passe en revue les perspectives offfertes par de nouveaux outils technologiques (imagerie, modélisation,...) pour l'étude des processus invasif et métastatique

The role of engineering approaches in analysing cancer invasion and metastasis

Zaman, Muhammad H.

In the past decade, novel materials, probes and tools have enabled fundamental and applied cancer researchers to take a fresh look at the complex problem of tumour invasion and metastasis. These new tools, which include imaging modalities, controlled but complex in vitro culture conditions, and the ability to model and predict complex processes in vivo, represent an integration of traditional with novel engineering approaches; and their potential effect on quantitatively understanding tumour [...]

Cet article présente les premiers résultats du projet "Sanger Institute Mouse Genetics" qui vise à produire de façon systématique des lignées de modèles murins dans lesquels un gène a été invalidé et à identifier les phénotypes associés

Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

White, Jacqueline K ; Gerdin, Anna-Karin ; Karp, Natasha A ; Ryder, Ed ; Buljan, Marija ; Bussell, James N ; Salisbury, Jennifer ; Clare, Simon ; Ingham, Neil J ; Podrini, Christine ; Houghton, Richard ; Estabel, Jeanne ; Bottomley, Joanna R ; Melvin, David G ; Sunter, David ; Adams, Niels C ; Tannahill, David ; Logan, Darren W. ; MacArthur, Daniel G. ; Flint, Jonathan ; Mahajan, Vinit B. ; Tsang, Stephen H. ; Smyth, Ian ; Watt, Fiona M. ; Skarnes, William C. ; Dougan, Gordon ; Adams, David J. ; Ramirez-Solis, Ramiro ; Bradley, Allan ; Steel, Karen P.

Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many [...]

Cet article passe en revue les travaux récents sur le rôle de la télomérase dans les mécanismes de cancérogenèse et de vieillissement

Telomerase at the intersection of cancer and aging

Bernardes de Jesus, Bruno ; Blasco, Maria A.

Although cancer and aging have been studied as independent diseases, mounting evidence suggests that cancer is an aging-associated disease and that cancer and aging share many molecular pathways. In particular, recent studies validated telomerase activation as a potential therapeutic target for age-related diseases; in addition, abnormal telomerase expression and telomerase mutations have been associated with many different types of human tumor. Here, we revisit the connection between [...]

Cet article présente une analyse exhaustive des variants génomiques identifiés par séquençage de l'exome entier dans les lignées cellulaires NCI-60

The Exomes of the NCI-60 Panel: A Genomic Resource for Cancer Biology and Systems Pharmacology

Abaan, Ogan D. ; Polley, Eric C. ; Davis, Sean R. ; Zhu, Yuelin J. ; Bilke, Sven ; Walker, Robert L. ; Pineda, Marbin ; Gindin, Yevgeniy ; Jiang, Yuan ; Reinhold, William C. ; Holbeck, Susan L. ; Simon, Richard M. ; Doroshow, James H. ; Pommier, Yves ; Meltzer, Paul S.

The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. This panel has generated the most extensive cancer pharmacology database worldwide. In addition, these cell lines have been intensely investigated, providing a unique platform for hypothesis-driven research focused on enhancing our understanding of tumor biology. Here, we report a comprehensive analysis of coding variants in the NCI-60 panel of cell lines identified by whole exome sequencing, [...]