Cet article passe en revue les travaux récents sur les mécanismes à l'origine d'un fort taux de mutations somatiques observé dans un grand nombre de tumeurs

Hypermutation in human cancer genomes: footprints and mechanisms

Roberts, Steven A. ; Gordenin, Dmitry A.

A role for somatic mutations in carcinogenesis is well accepted, but the degree to which mutation rates influence cancer initiation and development is under continuous debate. Recently accumulated genomic data have revealed that thousands of tumour samples are riddled by hypermutation, broadening support for the idea that many cancers acquire a mutator phenotype. This major expansion of cancer mutation data sets has provided unprecedented statistical power for the analysis of mutation spectra, [...]

Menée sur 1 479 cellules tumorales uniques isolées après prélèvement sur 6 patients atteints d'une leucémie lymphoblastique aiguë, cette étude identifie la séquence des événements génétiques qui se sont succédé au cours du développement de la maladie

Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics

Gawad, Charles ; Koh, Winston ; Quake, Stephen R.

Many cancers have substantial genomic heterogeneity within a given tumor, and to fully understand that diversity requires the ability to perform single cell analysis. We performed targeted sequencing of a panel of single nucleotide variants (SNVs), deletions, and IgH sequences in 1,479 single tumor cells from six acute lymphoblastic leukemia (ALL) patients. By accurately segregating groups of cooccurring mutations into distinct clonal populations, we identified codominant clones in the majority [...]

Menée à partir d'échantillons de moelle osseuse prélevés sur 50 patients atteints d'une leucémie lymphoblastique aiguë T, puis à l'aide d'un modèle murin, cette étude identifie un ensemble de micro-ARNs exerçant une fonction de suppresseur de tumeurs

Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia

Sanghvi, Viraj R. ; Mavrakis, Konstantinos J. ; Van der Meulen, Joni ; Boice, Michael ; Wolfe, Andrew L. ; Carty, Mark ; Mohan, Prathibha ; Rondou, Pieter ; Socci, Nicholas D. ; Benoit, Yves ; Taghon, Tom ; Van Vlierberghe, Pieter ; Leslie, Christina S. ; Speleman, Frank ; Wendel, Hans-Guido

The posttranscriptional control of gene expression by microRNAs (miRNAs) is highly redundant, and compensatory effects limit the consequences of the inactivation of individual miRNAs. This implies that only a few miRNAs can function as effective tumor suppressors. It is also the basis of our strategy to define functionally relevant miRNA target genes that are not under redundant control by other miRNAs. We identified a functionally interconnected group of miRNAs that exhibited a reduced [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le gène FBXO25 exerce une fonction de suppresseur de tumeurs dans les lymphomes à cellules du manteau

Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis

Baumann, Ursula ; Fernandez-Saiz, Vanesa ; Rudelius, Martina ; Lemeer, Simone ; Rad, Roland ; Knorn, Anna-Maria ; Slawska, Jolanta ; Engel, Katharina ; Jeremias, Irmela ; Li, Zhoulei ; Tomiatti, Viktoriya ; Illert, Anna-Lena ; Targosz, Bianca-Sabrina ; Braun, Martin ; Perner, Sven ; Leitges, Michael ; Klapper, Wolfram ; Dreyling, Martin ; Miething, Cornelius ; Lenz, Georg ; Rosenwald, Andreas ; Peschel, Christian ; Keller, Ulrich ; Kuster, Bernhard ; Bassermann, Florian

We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)FBXO25 ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, via la surexpression d'une ubiquitine ligase, le gène TRIM37 favorise le développement d'un cancer du sein

TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein

Bhatnagar, Sanchita ; Gazin, Claude ; Chamberlain, Lynn ; Ou, Jianhong ; Zhu, Xiaochun ; Tushir, Jogender S. ; Virbasius, Ching-Man ; Lin, Ling ; Zhu, Lihua J. ; Wajapeyee, Narendra ; Green, Michael R.

The TRIM37 (also known as MUL) gene is located in the 17q23 chromosomal region, which is amplified in up to ~40% of breast cancers. TRIM37 contains a RING finger domain, a hallmark of E3 ubiquitin ligases, but its protein substrate(s) is unknown. Here we report that TRIM37 mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. We find that in human breast cancer cell lines containing amplified 17q23, TRIM37 is upregulated and, reciprocally, the [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via l'activation de la signalisation Rac1, la protéine Sema3C favorise la survie des cellules souches de gliomes

Sema3C Promotes the Survival and Tumorigenicity of Glioma Stem Cells through Rac1 Activation

Man, Jianghong ; Shoemake, Jocelyn ; Zhou, Wenchao ; Fang, Xiaoguang ; Wu, Qiulian ; Rizzo, Anthony ; Prayson, Richard ; Bao, Shideng ; Rich, Jeremy N ; Yu, Jennifer S

Different cancer cell compartments often communicate through soluble factors to facilitate tumor growth. Glioma stem cells (GSCs) are a subset of tumor cells that resist standard therapy to contribute to disease progression. How GSCs employ a distinct secretory program to communicate with and nurture each other over the nonstem tumor cell (NSTC) population is not well defined. Here, we show that GSCs preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate [...]

Menée à l'aide de cellules souches embryonnaires, cette étude met en évidence le rôle joué par une mutation de l'histone H3.3, en coopération avec une perte du gène p53 et une activation de la signalisation PDGRA, dans la croissance tumorale d'un gliome infiltrant du tronc cérébral

Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation

Funato, Kosuke ; Major, Tamara ; Lewis, Peter W. ; Allis, C. David ; Tabar, Viviane

Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a human embryonic stem (ES) cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human ES cells, resulting in neoplastic [...]

Cet article passe en revue le rôle du récepteur aux hydrocarbures aromatiques dans la progression tumorale

Aryl hydrocarbon receptor ligands in cancer: friend and foe

Murray, Iain A. ; Patterson, Andrew D. ; Perdew, Gary H.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as 'dioxin'. AHR influences the major stages of tumorigenesis [mdash] initiation, promotion, progression and metastasis [mdash] and physiologically relevant AHR ligands are often formed during disease states or during heightened innate and adaptive immune responses. [...]

Menée à l'aide de modèles murins d'adénocarcinome du poumon, cette étude met en évidence des mécanismes par lesquels une glycoprotéine, la galectine-3, favorise le développement d'une niche métastatique

Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche

Reticker-Flynn, Nathan E ; Bhatia, Sangeeta N.

Metastasis is the leading cause of cancer-associated deaths. While dissemination of tumor cells likely occurs early in tumorigenesis, the constituents of the microenvironment play essential rate-limiting roles in determining whether these cells will form clinically-relevant tumors. Recent studies have uncovered many molecular factors that contribute to establishment of a pro-tumorigenic metastatic niche. Here, we demonstrate that galectin-3, whose expression has clinical associations with [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels l'expression du gène KAP1 favorise le processus métastatique d'un cancer du sein

KAP1 promotes proliferation and metastatic progression of breast cancer cells

Addison, Joseph ; Koontz, Colton ; Fugett, James H ; Creighton, Chad J. ; Chen, Dongquan ; Farrugia, Mark K. ; Padon, Renata R. ; Voronkova, Maria A. ; McLaughlin, Sarah L. ; Livengood, Ryan H. ; Lin, Chen-Chung ; Ruppert, J. Michael ; Pugacheva, Elena N. ; Ivanov, Alexey V.

KAP1 (TRIM28) is a transcriptional regulator in embryonic development that controls stem cell self-renewal, chromatin organization and the DNA damage response, acting as an essential co-repressor for KRAB family zinc finger proteins (KRAB-ZNF). To gain insight into the function of this large gene family, we developed an antibody that recognizes the conserved zinc fingers linker region (ZnFL) in multiple KRAB-ZNF. Here we report that the expression of many KRAB-ZNF along with active SUMOlyated [...]

Menée à l'aide de xénogreffes dérivées d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude de séquençage à l'échelle des cellules uniques met en évidence la dynamique des populations clonales après la greffe initiale

Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution

Eirew, Peter ; Steif, Adi ; Khattra, Jaswinder ; Ha, Gavin ; Yap, Damian ; Farahani, Hossein ; Gelmon, Karen ; Chia, Stephen ; Mar, Colin ; Wan, Adrian ; Laks, Emma ; Biele, Justina ; Shumansky, Karey ; Rosner, Jamie ; McPherson, Andrew ; Nielsen, Cydney ; Roth, Andrew J. L. ; Lefebvre, Calvin ; Bashashati, Ali ; de Souza, Camila ; Siu, Celia ; Aniba, Radhouane ; Brimhall, Jazmine ; Oloumi, Arusha ; Osako, Tomo ; Bruna, Alejandra ; Sandoval, Jose L. ; Algara, Teresa ; Greenwood, Wendy ; Leung, Kaston ; Cheng, Hongwei ; Xue, Hui ; Wang, Yuzhuo ; Lin, Dong ; Mungall, Andrew J. ; Moore, Richard ; Zhao, Yongjun ; Lorette, Julie ; Nguyen, Long ; Huntsman, David ; Eaves, Connie J. ; Hansen, Carl ; Marra, Marco A. ; Caldas, Carlos ; Shah, Sohrab P. ; Aparicio, Samuel

Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and [...]