A partir d'échantillons tumoraux prélevés sur 814 patients atteints d'un mélanome cutané primitif, cette étude suggère que la présence d'une mutation activatrice du gène RAC favorise la progression des mélanomes présentant un gène BRAF muté

Clinical and pathological associations of the activating RAC1 P29S mutation in primary cutaneous melanoma

Mar, Victoria J. ; Wong, Stephen Q. ; Logan, Aleksandra ; Nguyen, Trung ; Cebon, Jonathan ; Kelly, John ; Wolfe, Rory ; Dobrovic, Alexander ; McLean, Catriona ; McArthur, Grant A.

Activating mutations in the GTPase RAC1 are a recurrent event in cutaneous melanoma. We investigated the clinical and pathological associations of RAC1P29S in a cohort of 814 primary cutaneous melanomas with known BRAF and NRAS mutation status. The RAC1P29S mutation had a prevalence of 3.3% and was associated with increased thickness (OR=1.6 p=0.001), increased mitotic rate (OR=1.3 p=0.03), ulceration (OR=2.4 p=0.04), nodular subtype (OR=3.4 p=0.004) and nodal disease at diagnosis (OR=3.3 [...]

Menée dans le cadre du projet "The Cancer Genome Atlas" sur des échantillons de tumeurs du côlon et du rectum , cette étude met en évidence l'intérêt d'une analyse intégrée du protéome et du génome tumoraux pour interpréter les conséquences fonctionnelles des anomalies génomiques

Proteogenomic characterization of human colon and rectal cancer

Zhang, Bing ; Wang, Jing ; Wang, Xiaojing ; Zhu, Jing ; Liu, Qi ; Shi, Zhiao ; Chambers, Matthew C. ; Zimmerman, Lisa J. ; Shaddox, Kent F. ; Kim, Sangtae ; Davies, Sherri R. ; Wang, Sean ; Wang, Pei ; Kinsinger, Christopher R. ; Rivers, Robert C. ; Rodriguez, Henry ; Townsend, R. Reid ; Ellis, Matthew J. C. ; Carr, Steven A. ; Tabb, David L. ; Coffey, Robert J. ; Slebos, Robbert J. C. ; Liebler, Daniel C. ; the, Nci Cptac

Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between [...]

Menée initialement sur des échantillons de tissu mammaire et de sang prélevés sur 8 femmmes présentant un fibroadénome, puis validée sur 90 cas complémentaires de fibroadénomes, cette étude de séquençage de l'exome met en évidence de fréquentes mutations somatiques du gène MED12

Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma

Lim, Weng Khong ; Ong, Choon Kiat ; Tan, Jing ; Thike, Aye Aye ; Ng, Cedric Chuan Young ; Rajasegaran, Vikneswari ; Myint, Swe Swe ; Nagarajan, Sanjanaa ; Nasir, Nur Diyana Md ; McPherson, John R. ; Cutcutache, Ioana ; Poore, Gregory ; Tay, Su Ting ; Ooi, Wei Siong ; Tan, Veronique Kiak Mien ; Hartman, Mikael ; Ong, Kong Wee ; Tan, Benita K. T. ; Rozen, Steven G. ; Tan, Puay Hoon ; Tan, Patrick ; Teh, Bin Tean

Fibroadenomas are the most common breast tumors in women under 30 (refs. 1,2). Exome sequencing of eight fibroadenomas with matching whole-blood samples revealed recurrent somatic mutations solely in MED12, which encodes a Mediator complex subunit. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection, we show that MED12 [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en inhibant l'activation de la signalisation c-Myc, la prolactine prévient la formation d'un carcinome hépatocellulaire

Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice

Hartwell, Hadley J. ; Petrosky, Keiko Y. ; Fox, James G. ; Horseman, Nelson D. ; Rogers, Arlin B.

Women are more resistant to hepatocellular carcinoma (HCC) than men despite equal exposure to major risk factors, such as hepatitis B or C virus infection. Female resistance is hormone-dependent, as evidenced by the sharp increase in HCC incidence in postmenopausal women who do not take hormone replacement therapy. In rodent models sex-dimorphic HCC phenotypes are pituitary-dependent, suggesting that sex hormones act via the gonadal-hypophyseal axis. We found that the estrogen-responsive [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels une sous-expression du gène Sox4 favorise le processus de viellissement tout en réprimant la cancérogenèse

Sox4 Links Tumor Suppression to Accelerated Aging in Mice by Modulating Stem Cell Activation

Foronda, Miguel ; Martínez, Paula ; Schoeftner, Stefan ; Gómez-López, Gonzalo ; Schneider, Ralph ; Flores, Juana M ; Pisano, David G ; Blasco, Maria A

Sox4 expression is restricted in mammals to embryonic structures and some adult tissues, such as lymphoid organs, pancreas, intestine, and skin. During embryogenesis, Sox4 regulates mesenchymal and neural progenitor survival, as well as lymphocyte and myeloid differentiation, and contributes to pancreas, bone, and heart development. Aberrant Sox4 expression is linked to malignant transformation and metastasis in several types of cancer. To understand the role of Sox4 in the adult organism, we [...]

Menée in vitro, cette étude met en évidence un réseau de gènes qui, en lien avec le suppresseur de tumeurs p53, régulent la réponse à un stress cellulaire

A Comprehensive and High-Resolution Genome-wide Response of p53 to Stress

Chang, Gue Su ; Chen, Xiangyun Amy ; Park, Bongsoo ; Rhee, Ho Sung ; Li, Pingxin ; Han, Kang Hoo ; Mishra, Tejaswini ; Chan-Salis, Ka Yim ; Li, Yunfei ; Hardison, Ross C ; Wang, Yanming ; Pugh, B.  Franklin

Tumor suppressor p53 regulates transcription of stress-response genes. Many p53 targets remain undiscovered because of uncertainty as to where p53 binds in the genome and the fact that few genes reside near p53-bound recognition elements (REs). Using chromatin immunoprecipitation followed by exonuclease treatment (ChIP-exo), we associated p53 with 2,183 unsplit REs. REs were positionally constrained with other REs and other regulatory elements, which may reflect structurally organized p53 [...]

Menée à l'aide de six lignées cellulaires de lymphome hodgkinien, cette étude met en évidence le rôle joué par l'expression aberrante de plusieurs gènes FOX dans le développement de la maladie

Deregulated FOX genes in Hodgkin lymphoma

Nagel, Stefan ; Meyer, Corinna ; Kaufmann, Maren ; Drexler, Hans G. ; MacLeod, Roderick A. F.

FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en réduisant au silence l'expression du gène MLH1, l'histone déméthylase LSD1 joue un rôle oncogénique dans le cancer du côlon

Silencing of the DNA Mismatch Repair Gene MLH1 Induced by Hypoxic Stress in a Pathway Dependent on the Histone Demethylase LSD1

Lu, Yuhong ; Wajapeyee, Narendra ; Turker, Mitchell S ; Glazer, Peter M

Silencing of MLH1 is frequently seen in sporadic colorectal cancers. We show here that hypoxia causes decreased histone H3 lysine 4 (H3K4) methylation at the MLH1 promoter via the action of the H3K4 demethylases LSD1 and PLU-1 and promotes durable long-term silencing in a pathway that requires LSD1. Knockdown of LSD1 or its corepressor, CoREST, also prevents the resilencing (and associated cytosine DNA methylation) of the endogenous MLH1 promoter in RKO colon cancer cells following transient [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via l'activation du gène Rac, le micro-ARN miR-149 inhibe la formation de métastases pulmonaires d'un cancer du sein de type basal

miR-149 functions as a tumor suppressor by controlling breast epithelial cell migration and invasion

Bischoff, Annabell ; Huck, Bettina ; Keller, Bettina ; Strotbek, Michaela ; Schmid, Simone ; Boerries, Melanie ; Busch, Hauke ; Müller, Dafne ; Olayioye, Monilola A

Deregulated molecular signaling pathways are responsible for the altered adhesive, migratory and invasive properties of cancer cells. The different breast cancer subtypes are characterized by the expression of distinct microRNAs (miRNAs), short non-coding RNAs that post-transcriptionally modulate the expression of entire gene networks. Profiling studies have revealed down-regulation of miR-149 in basal breast cancer. Here we show that miR-149 expression severely impairs cell spreading, [...]

Cet article passe en revue les travaux récents sur le micro-environnement des métastases cérébrales

Role of the Neural Niche in Brain Metastatic Cancer

Termini, John ; Neman, Josh ; Jandial, Rahul

Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically, brain metastases were rarely investigated because patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la surexpression du récepteur TLR9 dans les cellules souches de gliome

TLR9 is Critical for Glioma Stem Cell Maintenance and Targeting

Herrmann, Andreas ; Cherryholmes, Gregory ; Schroeder, Anne ; Phallen, Jillian ; Alizadeh, Darya ; Xin, Hong ; Wang, Tianyi ; Lee, Heehyoung ; Lahtz, Christoph ; Swiderski, Piotr ; Armstrong, Brian ; Kowolik, Claudia ; Gallia, Gary L ; Lim, Michael ; Brown, Christine E. ; Badie, Behnam ; Forman, Stephen J. ; Kortylewski, Marcin ; Jove, Richard ; Yu, Hua

Understanding supports for cancer stem-like cells in malignant glioma may suggest therapeutic strategies for their elimination. Here we show that the Toll-like receptor TLR9 is elevated in glioma stem-like cells (GSC) where it contributes to glioma growth. TLR9 overexpression is regulated by STAT3 which was required for GSC maintenance. Stimulation of TLR9 with a CpG ligand (CpG ODN) promoted GSC growth, whereas silencing TLR9 expression abrogated GSC development. CpG-ODN treatment induced [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, dans les cellules de gliome, une surexpression de la galectine-1 inhibe l'action antitumorale des lymphocytes NK

Natural Killer Cells Eradicate Galectin-1 Deficient Glioma in the Absence of Adaptive Immunity

Baker, Gregory J. ; Chockley, Peter ; Yadav, Viveka Nand ; Doherty, Robert ; Ritt, Michael ; Sivaramakrishnan, Sivaraj ; Castro, Maria G. ; Lowenstein, Pedro R.

Natural killer (NK) cells safeguard against early tumor formation by destroying transformed target cells in a process referred to as NK immune surveillance. However, the immune escape mechanisms used by malignant brain tumors to subvert this innate type of immune surveillance remain unclear. Here we show that malignant glioma cells suppress NK immune surveillance by overexpressing the β-galactoside-binding lectin galectin-1. Conversely, galectin-1 deficient glioma cells could be eradicated by [...]

Cet article passe en revue les travaux récents sur le rôle joué par la sénescence cellulaire dans le développement tumoral, la fonction de suppresseur de tumeurs et la réponse thérapeutique

Inside and out: the activities of senescence in cancer

Perez-Mancera, Pedro A. ; Young, Andrew R. J. ; Narita, Masashi

The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is [...]

Cet article passe en revue les enjeux associés à la définition, en sciences de la vie et, en particulier, en recherches sur la biologie du cancer, d'un cadre de référence permettant d'assurer la reproductibilité des études précliniques

The Increasing Urgency for Standards in Basic Biologic Research

Freedman, Leonard P. ; Inglese, James

Research advances build upon the validity and reproducibility of previously published data and findings. Yet irreproducibility in basic biologic and preclinical research is pervasive in both academic and commercial settings. Lack of reproducibility has led to invalidated research breakthroughs, retracted articles, and aborted clinical trials. Concerns and requirements for transparent, reproducible, and translatable research are accelerated by the rapid growth of “post-publication peer review,” [...]