Cet article passe en revue les travaux récents ayant identifié des mutations de gènes conférant un avantage sélectif aux cellules tumorales dans divers types de cancer

Cancer Genome Landscapes

Vogelstein, Bert ; Papadopoulos, Nickolas ; Velculescu, Victor E. ; Zhou, Shibin ; Diaz, Luis A. ; Kinzler, Kenneth W.

Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these [...]

Menée sur 1 230 échantillons tumoraux prélevés sur des patients atteints d'une tumeur solide (60 types différents), cette étude met en évidence de fréquentes mutations de la séquence promotrice du gène TERT dans les gliomes et dans un sous-groupe de tumeurs dérivées de cellules à faible taux de renouvellement

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal

Killela, Patrick J. ; Reitman, Zachary J. ; Jiao, Yuchen ; Bettegowda, Chetan ; Agrawal, Nishant ; Diaz, Luis A. ; Friedman, Allan H. ; Friedman, Henry ; Gallia, Gary L. ; Giovanella, Beppino C. ; Grollman, Arthur P. ; He, Tong-Chuan ; He, Yiping ; Hruban, Ralph H. ; Jallo, George I. ; Mandahl, Nils ; Meeker, Alan K. ; Mertens, Fredrik ; Netto, George J. ; Rasheed, B. Ahmed ; Riggins, Gregory J. ; Rosenquist, Thomas A. ; Schiffman, Mark ; Shih, Ie-Ming ; Theodorescu, Dan ; Torbenson, Michael S. ; Velculescu, Victor E. ; Wang, Tian-Li ; Wentzensen, Nicolas ; Wood, Laura D. ; Zhang, Ming ; McLendon, Roger E. ; Bigner, Darell D. ; Kinzler, Kenneth W. ; Vogelstein, Bert ; Papadopoulos, Nickolas ; Yan, Hai

Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in [...]

Cet article passe en revue les travaux récents en génétique et génomique des cancers du pancréas et analyse les perspectives cliniques offertes par ces connaissances

Pancreatic cancer genomics: insights and opportunities for clinical translation

Makohon-Moore, Alvin ; Brosnan, Jacqueline ; Iacobuzio-Donahue, Christine

Pancreatic cancer is a highly lethal tumor type for which there are few viable therapeutic options. It is also caused by the accumulation of mutations in a variety of genes. These genetic alterations can be grouped into those that accumulate during pancreatic intraepithelial neoplasia (precursor lesions) and thus are present in all cells of the infiltrating carcinoma, and those that accumulate specifically within the infiltrating carcinoma during subclonal evolution, resulting in genetic [...]

Menée sur des échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un gliome intrinsèque diffus du pont, cette étude met en évidence un mécanisme par lequel une mutation du gène de l'histone H3 inhibe l'activité enzymatique du complexe PRC2

Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma

Lewis, Peter W. ; Müller, Manuel M. ; Koletsky, Matthew S. ; Cordero, Francisco ; Lin, Shu ; Banaszynski, Laura A. ; Garcia, Benjamin A. ; Muir, Tom W. ; Becher, Oren J. ; Allis, C. David

Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall H3K27me3 levels, and that histone H3K27M transgenes are sufficient to reduce H3K27me3 levels in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 [...]

Cet article passe en revue les travaux récents sur le rôle de facteurs de transcription et de régulateurs de la chromatine dans les diverses phases du développement d'un cancer

Epigenetic Reprogramming in Cancer

Suvà, Mario L. ; Riggi, Nicolo ; Bernstein, Bradley E.

The demonstration of induced pluripotency and direct lineage conversion has led to remarkable insights regarding the roles of transcription factors and chromatin regulators in mediating cell state transitions. Beyond its considerable implications for regenerative medicine, this body of work is highly relevant to multiple stages of oncogenesis, from the initial cellular transformation to the hierarchical organization of established malignancies. Here, we review conceptual parallels between the [...]

Menée sur 5 569 échantillons tumoraux prélevés sur des patients atteints d'une tumeur solide, puis in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le gène PDE4D favorise la croissance tumorale

Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Lin, De-Chen ; Xu, Liang ; Ding, Ling-Wen ; Sharma, Arjun ; Liu, Li-Zhen ; Yang, Henry ; Tan, Patrick ; Vadgama, Jay ; Karlan, Beth Y. ; Lester, Jenny ; Urban, Nicole ; Schummer, Michèl ; Doan, Ngan ; Said, Jonathan W. ; Sun, Hongmao ; Walsh, Martin ; Thomas, Craig J. ; Patel, Paresma ; Yin, Dong ; Chan, Daniel ; Koeffler, H. Phillip

Discovery of cancer genes through interrogation of genomic dosage is one of the major approaches in cancer research. In this study, we report that phosphodiesterase subtype 4D (PDE4D) gene was homozygously deleted in 198 cases of 5,569 primary solid tumors (3.56%), with most being internal microdeletions. Unexpectedly, the microdeletions did not result in loss of their gene products. Screening PDE4D expression in 11 different types of primary tumor samples (n = 165) with immunohistochemistry [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par plusieurs facteurs de transcription de la famille ETS dans les leucémies érythro-mégacaryocytaires

Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia

Tang, Jian Zhong ; Carmichael, Catherine L. ; Shi, Wei ; Metcalf, Donald ; Ng, Ashley P. ; Hyland, Craig D. ; Jenkins, Nancy A. ; Copeland, Neal G. ; Howell, Viive M. ; Zhao, Zhizhuang Joe ; Smyth, Gordon K. ; Kile, Benjamin T. ; Alexander, Warren S.

To define genetic lesions driving leukemia, we targeted cre-dependent Sleeping Beauty (SB) transposon mutagenesis to the blood-forming system using a hematopoietic-selective vav 1 oncogene (vav1) promoter. Leukemias of diverse lineages ensued, most commonly lymphoid leukemia and erythroleukemia. The inclusion of a transgenic allele of Janus kinase 2 (JAK2)V617F resulted in acceleration of transposon-driven disease and strong selection for erythroleukemic pathology with transformation of [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels la glycoprotéine de surface cellulaire CD44 favorise le développement d'une leucémie lymphocytaire chronique

CD44 regulates the apoptotic response and promotes disease development in chronic lymphocytic leukemia

Fedorchenko, Oleg ; Stiefelhagen, Marius ; Peer Zada, Abdul A. ; Barthel, Romy ; Mayer, Petra ; Eckei, Laura ; Breuer, Alexandra ; Crispatzu, Giuliano ; Rosen, Natascha ; Landwehr, Thomas ; Lilienthal, Nils ; Möllmann, Michael ; Montesinos-Rongen, Manuel ; Heukamp, Lukas ; Dürig, Jan ; Hallek, Michael ; Fingerle-Rowson, Günter ; Herling, Marco

The cell-surface glycoprotein CD44 is expressed in chronic lymphocytic leukemia (CLL), but its functional role in this disease is poorly characterized. We therefore investigated the contribution of CD44 to CLL in a murine disease model, the Eμ-TCL1 transgenic mouse, and in CLL patients. Surface CD44 increased during murine CLL development. CD44 ex-pression in human CLL was induced by stimulation with IL4/CD40L and by stroma cell contact. Engagement of CD44 by its natural ligands, hyaluronic [...]

Menée sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer du poumon, puis in vitro et in vivo, cette étude met en évidence le rôle joué par la kinase TPL2 dans la répression de la croissance tumorale

TPL2 kinase is a suppressor of lung carcinogenesis

Gkirtzimanaki, Katerina ; Gkouskou, Kalliopi K. ; Oleksiewicz, Urszula ; Nikolaidis, Georgios ; Vyrla, Dimitra ; Liontos, Michalis ; Pelekanou, Vassiliki ; Kanellis, Dimitris C. ; Evangelou, Kostantinos ; Stathopoulos, Efstathios N. ; Field, John K. ; Tsichlis, Philip N. ; Gorgoulis, Vassilis ; Liloglou, Triantafillos ; Eliopoulos, Aristides G.

Lung cancer is a heterogeneous disease at both clinical and molecular levels, posing conceptual and practical bottlenecks in defining key pathways affecting its initiation and progression. Molecules with a central role in lung carcinogenesis are likely to be targeted by multiple deregulated pathways and may have prognostic, predictive, and/or therapeutic value. Here, we report that Tumor Progression Locus 2 (TPL2), a kinase implicated in the regulation of innate and adaptive immune responses, [...]

Cet article passe en revue les travaux récents sur le rôle de la voie de signalisation Hedgehog dans le développement d'un cancer du sein et analyse les perspectives thérapeutiques offertes par ces connaissances

The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy

Hui, Mun ; Cazet, Aurelie ; Nair, Radhika ; Watkins, D ; O'Toole, Sandra ; Swarbrick, Alexander

Despite the progress achieved in breast cancer screening and therapeutic innovations, the basal-like subtype of breast cancer (BLBC) still represents a particular clinical challenge. In order to make an impact on survival in this type of aggressive breast cancer, new targeted therapeutic agents are urgently needed. Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent [...]

Cet article passe en revue les travaux récents sur les différents rôles du microenvironnement dans le développement de métastases hépatiques

The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications

Van den Eynden, Gert G. ; Majeed, Ali W. ; Illemann, Martin ; Vermeulen, Peter B. ; Bird, Nigel C. ; Høyer-Hansen, Gunilla ; Eefsen, Rikke Løvendahl ; Reynolds, Andrew R. ; Brodt, Pnina

The liver is host to many metastatic cancers, particularly colorectal cancer, for which the last 2 decades have seen major advances in diagnosis and treatment. The liver is a vital organ, and the extent of its involvement with metastatic disease is a major determinant of survival. Metastatic cells arriving in the liver via the bloodstream encounter the microenvironment of the hepatic sinusoid. The interactions of the tumor cells with hepatic sinusoidal and extrasinusoidal cells (endothelial, [...]

Cet article passe en revue les travaux récents sur le rôle de la bêta-caténine dans le processus métastatique d'un mélanome

A Wnt-er Migration: The Confusing Role of {beta}-Catenin in Melanoma Metastasis

Webster, Marie R. ; Weeraratna, Ashani T.

Wnt signaling in melanoma is complex, requiring the coordinate expression of multiple players. Depending on the context of receptors and co-receptors that are present, Wnt proteins may signal through either canonical or noncanonical pathways. The role of

Menée in vitro et in vivo, cette étude met en évidence un mécanisme métabolique par lequel la glutamine favorise la croissance d'un adénocarcinome canalaire du pancréas

Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway

Son, Jaekyoung ; Lyssiotis, Costas A. ; Ying, Haoqiang ; Wang, Xiaoxu ; Hua, Sujun ; Ligorio, Matteo ; Perera, Rushika M. ; Ferrone, Cristina R. ; Mullarky, Edouard ; Shyh-Chang, Ng ; Kang, Ya 'an ; Fleming, Jason B. ; Bardeesy, Nabeel ; Asara, John M. ; Haigis, Marcia C. ; DePinho, Ronald A. ; Cantley, Lewis C. ; Kimmelman, Alec C.

Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel les cellules endothéliales du microenvironnement tumoral favorisent le processus métastatique d'un cancer de la prostate

Endothelial cells enhance prostate cancer metastasis via IL6→androgen receptor→TGFβ→MMP9 signals

Wang, Xiaohai ; Lee, Soo Ok ; Xia, Shujie ; Jiang, Qi ; Luo, Jie ; Li, Lei ; Yeh, Shuyuan ; Chang, Chawnshang

While the potential roles of endothelial cells (ECs) in the microvascules of prostate cancer (PCa) during angiogenesis have been documented, their direct impacts on the PCa metastasis remain unclear. We found that the CD31-positive and CD34-positive ECs are increased in PCa compared to the normal tissues and these ECs cells were decreased upon castration, gradually recovered with time, and become increased after PCa progresses into the castration resistant stage, suggesting a potential linkage [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels le facteur de transcription FoxA1 inhibe le processus métastatique d'un cancer de la prostate

Androgen receptor-independent function of FoxA1 in prostate cancer metastasis

Jin, Hong-Jian ; Zhao, Jonathan C. ; Ogden, Irene ; Bergan, Raymond ; Yu, Jindan

FoxA1 (FOXA1) is a pioneering transcription factor of the androgen receptor (AR) that is indispensable for the lineage-specific gene expression of the prostate. To date, there have been conflicting reports on the role of FoxA1 in prostate cancer progression and prognosis. With recent discoveries of recurrent FoxA1 mutations in human prostate tumors, comprehensive understanding of FoxA1 function has become very important. Here, through genomic analysis we reveal that FoxA1 regulates two distinct [...]

Menée à l'aide d'un modèle murin et sur des échantillons tumoraux prélevés chez des patientes atteintes d'un cancer métastatique du sein, cette étude met en évidence des mécanismes par lesquels l'expression d'une enzyme impliquée dans la synthèse du collagène, la prolyl hydroxylase, favorise le processus métastatique

Collagen Prolyl Hydroxylases are Essential for Breast Cancer Metastasis

Gilkes, Daniele M. ; Chaturvedi, Pallavi ; Bajpai, Saumendra ; Wong, Carmen Chak-Lui ; Wei, Hong ; Pitcairn, Stephen ; Hubbi, Maimon E. ; Wirtz, Denis ; Semenza, Gregg L.

Metastasis is the leading cause of death among patients with breast cancer. Understanding the role of the extracellular matrix in the metastatic process may lead to the development of improved therapies for cancer patients. Intratumoral hypoxia is found in the majority of breast cancers and is associated with an increased risk of metastasis and patient mortality. Here we demonstrate that hypoxia-inducible factor 1 activates the transcription of genes encoding collagen prolyl hydroxylases that [...]

Menée à l'aide de modèles murins et d'outils d'imagerie, cette étude met en évidence l'évolution de paramètres biochimiques liés à l'activité d'oxydo-réduction au cours de la progression d'un gliome ou d'un neuroblastome

Tissue redox activity as a hallmark of carcinogenesis: from early to terminal stages of cancer

Bakalova, Rumiana ; Zhelev, Zhivko ; Aoki, Ichio ; Saga, Tsuneo

Purpose: The study aimed to clarify the dynamics of tissue redox activity (TRA) in cancer progression and assess the importance of this parameter for therapeutic strategies. Experimental design: The experiments were conducted on brain tissues of neuroblastoma-bearing, glioma-bearing and healthy mice. TRA was visualized in vivo by nitroxide-enhanced magnetic resonance imaging (MRI) on anesthetized animals or in vitro by electron paramagnetic resonance (EPR) spectroscopy on isolated tissue [...]

Cette étude présente une méthode d'analyse statistique pour détecter, à partir de données produites par un séquençage de nouvelle génération, des différences dans la méthylation de loci à l'échelle du génome, puis évalue son intérêt en l'appliquant à des données sur la leucémie lymphocytaire chronique

A Method to Detect Differentially Methylated Loci With Next-Generation Sequencing

Xu, Hongyan ; Podolsky, Robert H. ; Ryu, Duchwan ; Wang, Xiaoling ; Su, Shaoyong ; Shi, Huidong ; George, Varghese

Epigenetic changes, especially DNA methylation at CpG loci have important implications in cancer and other complex diseases. With the development of next-generation sequencing (NGS), it is feasible to generate data to interrogate the difference in methylation status for genome-wide loci using case-control design. However, a proper and efficient statistical test is lacking. There are several challenges. First, unlike methylation experiments using microarrays, where there is one measure of [...]

Cette étude évalue l'intérêt de colosphères ex vivo pour le développement préclinique de traitements d'un cancer colorectal

A short-term colorectal cancer sphere culture as a relevant tool for human cancer biology investigation

Weiswald, L. B. ; Richon, S. ; Massonnet, G. ; Guinebretiere, J. M. ; Vacher, S. ; Laurendeau, I. ; Cottu, P. ; Marangoni, E. ; Nemati, F. ; Validire, P. ; Bellet, D. ; Bieche, I. ; Dangles-Marie, V.

Background: Ex vivo colospheres have been previously characterised as a colorectal cancer (CRC) well-rounded multicellular model, exclusively formed by carcinoma cells, and derived from fresh CRC tissue after mechanical dissociation. The ability to form colospheres was correlated with tumour aggressiveness. Their three-dimensional conformation prompted us to further investigate their potential interest as a preclinical cancer tool. Methods: Patient-derived CRC xenografts were used to produce [...]

Cette étude évalue l'intérêt d'un modèle ex vivo tridimensionnel de sarcome d'Ewing pour le développement préclinique de traitements des sarcomes osseux

Modeling Ewing sarcoma tumors in vitro with 3D scaffolds

Fong, Eliza Li Shan ; Lamhamedi-Cherradi, Salah-Eddine ; Burdett, Emily ; Ramamoorthy, Vandhana ; Lazar, Alexander J. ; Kasper, F. Kurtis ; Farach-Carson, Mary C. ; Vishwamitra, Deeksha ; Demicco, Elizabeth G. ; Menegaz, Brian A. ; Amin, Hesham M. ; Mikos, Antonios G. ; Ludwig, Joseph A.

The pronounced biological influence of the tumor microenvironment on cancer progression and metastasis has gained increased recognition over the past decade, yet most preclinical antineoplastic drug testing is still reliant on conventional 2D cell culture systems. Although monolayer cultures recapitulate some of the phenotypic traits observed clinically, they are limited in their ability to model the full range of microenvironmental cues, such as ones elicited by 3D cell–cell and [...]