Menée sur 4 623 échantillons tumoraux prélevés sur des patients atteints d'un cancer (13 localisations différentes), cette étude analyse la fréquence des mutations de 34 facteurs régulateurs de la chromatine en fonction de la localisation de la tumeur

The mutational landscape of chromatin regulatory factors across 4623 tumor samples

Gonzalez-Perez, Abel ; Jene-Sanz, Alba ; Lopez-Bigas, Nuria

BACKGROUND:Chromatin regulatory factors are emerging as important genes in cancer development and are regarded as interesting candidates for novel targets for cancer treatment. However, we lack a comprehensive understanding of the role of this group of genes in different cancer types. RESULTS:We have analyzed 4623 tumor samples from thirteen anatomical sites to determine which chromatin regulatory factors are candidate drivers in these different sites. We identify 34 chromatin regulatory [...]

Menée initialement sur 115 lignées cellulaires, puis à l'aide de xénogreffes et d'un séquençage de plus de 1 000 génomes de cancers pédiatriques, cette étude met en évidence la présence fréquente d'une altération du gène NSD2, qui code une méthyltransférase, dans certaines leucémies lymphoblastiques aiguës

Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia

Jaffe, Jacob D. ; Wang, Yan ; Chan, Ho Man ; Zhang, Jinghui ; Huether, Robert ; Kryukov, Gregory V. ; Bhang, Hyo-eun C. ; Taylor, Jordan E. ; Hu, Min ; Englund, Nathan P. ; Yan, Feng ; Wang, Zhaofu ; Robert McDonald Iii, E. ; Wei, Lei ; Ma, Jing ; Easton, John ; Yu, Zhengtian ; deBeaumount, Rosalie ; Gibaja, Veronica ; Venkatesan, Kavitha ; Schlegel, Robert ; Sellers, William R. ; Keen, Nicholas ; Liu, Jun ; Caponigro, Giordano ; Barretina, Jordi ; Cooke, Vesselina G. ; Mullighan, Charles ; Carr, Steven A. ; Downing, James R. ; Garraway, Levi A. ; Stegmeier, Frank

Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a [...]

Cet article passe en revue les travaux récents sur le rôle du gène ALK dans les cancers

Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Hallberg, Bengt ; Palmer, Ruth H.

The burgeoning field of anaplastic lymphoma kinase (ALK) in cancer encompasses many cancer types, from very rare cancers to the more prevalent non-small-cell lung cancer (NSCLC). The common activation of ALK has led to the use of the ALK tyrosine kinase inhibitor (TKI) crizotinib in a range of patient populations and to the rapid development of second-generation drugs targeting ALK. In this Review, we discuss our current understanding of ALK function in human cancer and the implications for [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la surexpression du gène SALL4 favorise le développement d'une leucémie myéloïde aiguë

A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis

Li, Ailing ; Yang, Youyang ; Gao, Chong ; Lu, Jiayun ; Jeong, Ha-Won ; Liu, Bee H. ; Tang, Ping ; Yao, Xiaopan ; Neuberg, Donna ; Huang, Gang ; Tenen, Daniel G. ; Chai, Li

The embryonic self-renewal factor SALL4 has been implicated in the development of human acute myeloid leukemia (AML). Transgenic mice expressing the human SALL4B allele develop AML, which indicates that this molecule contributes to leukemia development and maintenance. However, the underlying mechanism of SALL4-dependent AML progression is unknown. Using SALL4B transgenic mice, we observed that HoxA9 was significantly upregulated in SALL4B leukemic cells compared with wild-type controls. [...]

Menée in vitro, in vivo et à l'aide de 101 échantillons tumoraux prélevés sur des patients atteints d'un cancer de l'estomac, cette étude met en évidence des mécanismes par lesquels, en favorisant une transition épithélio-mésenchymateuse, l'histone déméthylase JMJD2B joue un rôle déterminant dans les processus invasif et métastatique

JMJD2B promotes epithelial-mesenchymal transition by cooperating with β-catenin and enhances gastric cancer metastasis

Zhao, Li ; Li, Wenjuan ; Zang, Wen ; Liu, Zhifang ; Xu, Xia ; Yu, Han ; Yang, Qing ; Jia, Jihui

Purpose: This study investigated the role of histone demethylase Jumonji domain-containing protein 2B (JMJD2B) in promoting epithelial-mesenchymal transition (EMT) and underlying molecular mechanisms in the progression of gastric cancer (GC). Experimental Design: The induction of EMT by JMJD2B in GC cells and its underlying mechanisms were examined by a series of assays. In-vivo and in-vitro assays were performed to clarify invasive potential of JMJD2B in GC cells. The expression dynamics of [...]

Cet article passe en revue les travaux récents sur le rôle d'excroissances membranaires appelées invadopodia dans les processus invasif et métastatique

Invading one step at a time: the role of invadopodia in tumor metastasis

Paz, H. ; Pathak, N. ; Yang, J.

The ability to degrade extracellular matrix is critical for tumor cells to invade and metastasize. Recent studies show that tumor cells use specialized actin-based membrane protrusions termed invadopodia to perform matrix degradation. Invadopodia provide an elegant way for tumor cells to precisely couple focal matrix degradation with directional movement. Here we discuss several key components and regulators of invadopodia that have been uniquely implicated in tumor invasion and metastasis. [...]

Menée sur des échantillons de tumeurs primitives et de métastases prélevés sur des patients atteints d'un mélanome métastatique, puis à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels deux paires de facteurs de transcription induisant une transition épithélio-mésenchymateuse, ZEB1/TWIST1 et SEB2/SNAIL2, jouent des rôles opposés dans le développement de la maladie

A Switch in the Expression of Embryonic EMT-Inducers Drives the Development of Malignant Melanoma

Caramel, Julie ; Papadogeorgakis, Eftychios ; Hill, Louise ; Browne, Gareth J ; Richard, Geoffrey ; Wierinckx, Anne ; Saldanha, Gerald ; Osborne, Joy ; Hutchinson, Peter ; Tse, Gina ; Lachuer, Joël ; Puisieux, Alain ; Pringle, J.  Howard ; Ansieau, Stéphane ; Tulchinsky, Eugene

Aberrant expression of embryonic epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) in epithelial cells triggers EMT, neoplastic transformation, stemness, and metastatic dissemination. We found that regulation and functions of EMT-TFs are different in malignant melanoma. SNAIL2 and ZEB2 transcription factors are expressed in normal melanocytes and behave as tumor-suppressor proteins by activating an MITF-dependent melanocyte differentiation program. In response to [...]

Cet article passe en revue les travaux récents sur le processus métastatique des mélanomes

Why Is Melanoma So Metastatic?

Braeuer, Russell R. ; Watson, Ian R. ; Wu, Chang-Jiun ; Mobley, Aaron K. ; Kamiya, Takafumi ; Shoshan, Einav ; Bar-Eli, Menashe

Malignant melanoma is one of the most aggressive cancers and can disseminate from a relatively small primary tumor and metastasize to multiple sites, including the lung, liver, brain, bone, and lymph nodes. Elucidating the molecular and genetic changes that take place during the metastatic process has led to a better understanding of why melanoma is so metastatic. Herein, we describe the unique features that distinguish melanoma from other solid tumors and contribute to the malignant phenotype [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels un long ARN non codant, SChLAP1, favorise les processus invasif et métastatique d'un cancer de la prostate

The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex

Prensner, John R. ; Iyer, Matthew K. ; Sahu, Anirban ; Asangani, Irfan A. ; Cao, Qi ; Patel, Lalit ; Vergara, Ismael A. ; Davicioni, Elai ; Erho, Nicholas ; Ghadessi, Mercedeh ; Jenkins, Robert B. ; Triche, Timothy J. ; Malik, Rohit ; Bedenis, Rachel ; McGregor, Natalie ; Ma, Teng ; Chen, Wei ; Han, Sumin ; Jing, Xiaojun ; Cao, Xuhong ; Wang, Xiaoju ; Chandler, Benjamin ; Yan, Wei ; Siddiqui, Javed ; Kunju, Lakshmi P. ; Dhanasekaran, Saravana M. ; Pienta, Kenneth J. ; Feng, Felix Y. ; Chinnaiyan, Arul M.

Prostate cancers remain indolent in the majority of individuals but behave aggressively in a minority. The molecular basis for this clinical heterogeneity remains incompletely understood. Here we characterize a long noncoding RNA termed SChLAP1 (second chromosome locus associated with prostate-1; also called LINC00913) that is overexpressed in a subset of prostate cancers. SChLAP1 levels independently predict poor outcomes, including metastasis and prostate cancer–specific mortality. In vitro [...]

Cet article passe en revue les travaux récents relatifs aux mécanismes d'immunosurveillance impliqués dans la régulation du processus métastatique d'un cancer du sein

The Emerging Role of Immunosurveillance in Dictating Metastatic Spread in Breast Cancer

Slaney, Clare Y. ; Rautela, Jai ; Parker, Belinda S.

It is now well known that the immune system can recognize transformed cells and control the initiation and growth of some cancers, a process termed tumor immunosurveillance. Key regulators of this process have been described in the primary tumor setting, where the balance of protumor and antitumor responses dictates tumor initiation and progression. Accumulating evidence suggests that immunosurveillance may also be critical for regulating metastatic spread, the most fatal aspect of cancer, and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la cytokine CD95L, lorsqu'elle est clivée par des métalloprotéases, favorise le processus métastatique d'un cancer du sein triplement négatif

CD95L cell surface cleavage triggers a pro-metastatic signaling pathway in triple negative breast cancer

Malleter, Marine ; Tauzin, Sebastien ; Bessede, Alban ; Castellano, Remy ; Goubard, Armelle ; Godey, Florence ; Leveque, Jean ; Jezequel, Pascal ; Campion, Loic ; Campone, Mario ; Ducret, Thomas ; MacGrogan, Gaëtan ; Debure, Laure ; Collette, Yves ; Vacher, Pierre ; Legembre, Patrick

Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors and HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this risk is not understood. Here we report that serum levels of CD95L are higher in TNBC patients compared to other breast cancer patients. Metalloprotease-mediated cleavage of CD95L expressed by endothelial cells surrounding tumors generates a gradient that promotes cell motility, due to formation of an [...]

Cet article passe en revue les travaux récents sur l'hypothèse des cellules souches cancéreuses dans les tumeurs solides

Unravelling cancer stem cell potential

Beck, Benjamin ; Blanpain, Cedric

The maintenance and repair of many adult tissues are ensured by stem cells (SCs), which reside at the top of the cellular hierarchy of these tissues. Functional assays, such as in vitro clonogenic assays, transplantation and in vivo lineage tracing, have been used to assess the renewing and differentiation potential of normal SCs. Similar strategies have suggested that solid tumours may also be hierarchically organized and contain cancer SCs (CSCs) that sustain tumour growth and relapse after [...]

Cet article passe en revue les travaux récents sur les outils de cartographie de l'épigénome

Mapping Human Epigenomes

Rivera, Chloe M ; Ren, Bing

As the second dimension to the genome, the epigenome contains key information specific to every type of cells. Thousands of human epigenome maps have been produced in recent years thanks to rapid development of high throughput epigenome mapping technologies. In this review, we discuss the current epigenome mapping toolkit and utilities of epigenome maps. We focus particularly on mapping of DNA methylation, chromatin modification state, and chromatin structures, and emphasize the use of [...]

Cet article passe en revue les travaux récents suggérant l'intérêt d'étudier les mélanomes se développant spontanément chez les chiens pour mieux comprendre le rôle des voies de signalisation dans le développement d'un mélanome non lié aux rayonnements ultra-violets chez les humains

Naturally occurring melanomas in dogs as models for non-UV pathways of human melanomas

Gillard, Marc ; Cadieu, Edouard ; De Brito, Clotilde ; Abadie, Jérôme ; Vergier, Béatrice ; Devauchelle, Patrick ; Degorce, Frédérique ; Dréano, Stephane ; Primot, Aline ; Dorso, Laetitia ; Lagadic, Marie ; Galibert, Francis ; Hédan, Benoit ; Galibert, Marie-Dominique ; André, Catherine

Spontaneously occurring melanomas are frequent in dogs. They appear at the same localizations as in humans, i.e. skin, mucosal sites, nail matrix and eyes. They display variable behaviors: tumors at oral localizations are more frequent and aggressive than at other anatomical sites. Interestingly, dog melanomas are associated with strong breed predispositions and overrepresentation of black-coated dogs. Epidemiological analysis of 2350 affected dogs showed that poodles are at high risk of [...]