A partir de 55 échantillons de tissu tumoral et 10 échantillons de tissu sain adjacent prélevés sur des patientes atteintes d'un cancer du sein, cette étude identifie la présence de fusions de gènes, notamment dans les échantillons de tumeurs HER2+

Genomic hotspots but few recurrent fusion genes in breast cancer

Fimereli, Danai ; Fumagalli, Debora ; Brown, David ; Gacquer, David ; Rothe, Francoise ; Salgado, Roberto ; Larsimont, Denis ; Sotiriou, Christos ; Detours, Vincent

The advent of next generation sequencing technologies has boosted the interest in exploring the role of fusion genes in the development and progression of solid tumors. In breast cancer, most of the detected gene fusions seem to be “passenger” events while the presence of recurrent and driver fusions is still under study. We performed RNA sequencing in 55 well-characterized breast cancer samples and 10 adjacent normal breast tissues, complemented by an analysis of SNP array data. We explored [...]

A partir d'échantillons de tumeurs primitives et de métastases prélevés sur une cohorte initiale de 10 patientes atteintes d'un cancer du sein, puis sur une cohorte complémentaire de 20 patientes, cette étude met notamment en évidence la présence de mutations des gènes de la famille AKAP dans les métastases

Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs)

Kjällquist, Una ; Erlandsson, Rikard ; Tobin, Nicholas P. ; Alkodsi, Amjad ; Ullah, Ikram ; Stålhammar, Gustav ; Karlsson, Eva ; Hatschek, Thomas ; Hartman, Johan ; Linnarsson, Sten ; Bergh, Jonas

Background : Tumor heterogeneity in breast cancer tumors is today widely recognized. Most of the available knowledge in genetic variation however, relates to the primary tumor while metastatic lesions are much less studied. Many studies have revealed marked alterations of standard prognostic and predictive factors during tumor progression. Characterization of paired primary- and metastatic tissues should therefore be fundamental in order to understand mechanisms of tumor progression, clonal [...]

Menée sur des lignées cellulaires cancéreuses, cette étude met en évidence des mécanismes par lesquels, en se liant aux pseudokinases KSR1 et KSR2, la protéine MEK favorise l'activation de la kinase BRAF

MEK drives BRAF activation through allosteric control of KSR proteins

Lavoie, Hugo ; Sahmi, Malha ; Maisonneuve, Pierre ; Marullo, Sara A. ; Thevakumaran, Neroshan ; Jin, Ting ; Kurinov, Igor ; Sicheri, Frank ; Therrien, Marc

RAF family kinases have prominent roles in cancer. Their activation is dependent on dimerization of their kinase domains, which has emerged as a hindrance for drug development. In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK). Kinase suppressor of Ras [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels des anomalies dans les séquences amplificatrices de certains gènes favorisent le développement d'une leucémie

Enhancer dysfunction in leukemia

Bhagwat, Anand S. ; Lu, Bin ; Vakoc, Christopher R.

Hematopoietic cancers are often initiated by deregulation of the transcriptional machinery. Prominent among such regulators are the sequence-specific DNA-binding transcription factors (TFs), which bind to enhancer and promoter elements in the genome to control gene expression through the recruitment of cofactors. Remarkably, perturbing the function of even a single TF or cofactor can modulate the active enhancer landscape of a cell and, conversely, knowledge of the enhancer configuration can be [...]

Menée in vitro et à l'aide d'un modèle murin avec mutation du gène Apc et absence de la protéine IKK-alpha dans les cellules épithéliales de l'intestin, cette étude montre que cette protéine est nécessaire au développement des cellules tumorales

IKK-alpha is required in the intestinal epithelial cells for tumour stemness

Colomer, Carlota ; Margalef, Pol ; Gonzalez, Jessica ; Vert, Anna ; Bigas, Anna ; Espinosa, Lluis

Background : Colorectal cancer is a common cause of death in developed countries. Progression from adenoma to invasive carcinoma requires accumulation of mutations starting with the Adenomatous Polyposis Coli (Apc) gene. NF-

Menée sur des lignées cellulaires cancéreuses et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels un micro-ARN sécrété par les cellules cancéreuses (hsa-miR-940) favorise la formation de métastases osseuses

Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A

Hashimoto, Kyoko ; Ochi, Hiroki ; Sunamura, Satoko ; Kosaka, Nobuyoshi ; Mabuchi, Yo ; Fukuda, Toru ; Yao, Kenta ; Kanda, Hiroaki ; Ae, Keisuke ; Okawa, Atsushi ; Akazawa, Chihiro ; Ochiya, Takahiro ; Futakuchi, Mitsuru ; Takeda, Shu ; Sato, Shingo

Prostate cancer is one of most common cancers in men worldwide, and osteoblastic bone metastasis is frequently observed in prostate cancer patients. However, the mechanisms responsible for the predominantly osteoblastic phenotype have not been fully elucidated. Cancer-secreted microRNAs (miRNAs) were recently shown to be significant in the modification of the tumor microenvironment. Here, hsa-miR-940, which was highly secreted by prostate cancer cells, promoted osteogenic differentiation of [...]

Cet article passe en revue les travaux récents sur le rôle joué par l'hétérogénéité génétique intra-tumorale dans le processus métastatique

Genetic insights into the morass of metastatic heterogeneity

Hunter, Kent W. ; Amin, Ruhul ; Deasy, Sarah ; Ha, Ngoc-Han ; Wakefield, Lalage

Tumour heterogeneity poses a substantial problem for the clinical management of cancer. Somatic evolution of the cancer genome results in genetically distinct subclones in the primary tumour with different biological properties and therapeutic sensitivities. The problem of heterogeneity is compounded in metastatic disease owing to the complexity of the metastatic process and the multiple biological hurdles that the tumour cell must overcome to establish a clinically overt metastatic lesion. New [...]

Cet article passe en revue les travaux récents ayant permis de mettre en oeuvre une approche évolutionniste pour étudier le développement d'un lymphome folliculaire

From genetics to the clinic: a translational perspective on follicular lymphoma

Huet, Sarah ; Sujobert, Pierre ; Salles, Gilles

Follicular lymphoma (FL) is the most frequent indolent B cell lymphoma and is still considered to be incurable. In recent years, whole-exome sequencing studies of large cohorts of patients have greatly improved our knowledge of the FL mutational landscape. Moreover, the prolonged evolution of this disease has enabled some insights regarding the early pre-lymphoma lesions as well as the clonal evolution after treatment, allowing an evolutionary perspective on lymphomagenesis. Deciphering the [...]

Menée sur des lignées cellulaires de cancer de l'ovaire, cette étude identifie une population cellulaire susceptible d'engendrer des cellules souches cancéreuses contribuant à l'hétérogénéité intratumorale

A distinct oncogenerative multinucleated cancer cell serves as a source of stemness and tumor heterogeneity

Diaz-Carballo, David ; Saka, Sahitya ; Klein, Jacqueline ; Rennkamp, Tobias ; Acikelli, Ali Haydar ; Malak, Sascha ; Jastrow, Holger ; Wennemuth, Gunther ; Tempfer, Clemens B. ; Schmitz, Inge ; Tannapfel, Andrea ; Strumberg, Dirk

The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiological stemness of the resulting cell populations. Here we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy refractory ovarian tumors, which generate and gestate daughter generation Gn-cells intracytoplasmically. Release of Gn-cells [...]

Menée à l'aide de xénogreffes de lignées cellulaires de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels, en facilitant la synthèse des androgènes à l'intérieur des tumeurs, le récepteur nucléaire LRH-1 favorise la croissance d'une tumeur résistante à la castration

Nuclear receptor LRH-1 functions to promote castration-resistant growth of prostate cancer via its promotion of intratumoral androgen biosynthesis

Xiao, Lijia ; Wang, Yuliang ; Xu, Kexin ; Hu, Hao ; Xu, Zhenyu ; Wu, Dinglan ; Wang, Zhu ; You, Wenxing ; Ng, Chi-Fai ; Yu, Shan ; Chan, Franky Leung

Targeting of steroidogenic enzymes (e.g. abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here we report that [...]

Menée à l'aide d'un modèle murin de carcinome lobulaire invasif métastatique, cette étude met en évidence le rôle joué par les facteurs de transcription FOXO dans la croissance tumorale et le processus métastatique

FOXO transcription factors both suppress and support breast cancer progression

Hornsveld, Marten ; Smits, Lydia M. ; Meerlo, Maaike ; van Amersfoort, Miranda ; Groot Koerkamp, Marian J. ; van Leenen, Dik ; Kloet, David E. ; Holstege, Frank C. ; Derksen, Patrick W. B. ; Burgering, Boudewijn M. T. ; Dansen, Tobias B.

FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular [...]

Menée in vitro et in vivo sur des modèles de cancer du sein, cette étude met en évidence des mécanismes par lesquels la biodisponibilité d'un seul acide aminé, l'asparagine, favorise le processus métastatique

Asparagine bioavailability governs metastasis in a model of breast cancer

Knott, Simon R. V. ; Wagenblast, Elvin ; Khan, Showkhin ; Kim, Sun Y. ; Soto, Mar ; Wagner, Michel ; Turgeon, Marc-Olivier ; Fish, Lisa ; Erard, Nicolas ; Gable, Annika L. ; Maceli, Ashley R. ; Dickopf, Steffen ; Papachristou, Evangelia K. ; D’Santos, Clive S. ; Carey, Lisa A. ; Wilkinson, John E. ; Harrell, J. Chuck ; Perou, Charles M. ; Goodarzi, Hani ; Poulogiannis, George ; Hannon, Gregory J.

Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites1. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient’s primary tumour was most strongly [...]

Menée in vitro et in vivo sur des modèles de cancer invasif de la vessie, cette étude met en évidence des mécanismes par lesquels, en interagissant avec la protéine issue d'un gène p53 muté et avec le récepteur EGFR, la protéine DDX31 favorise le processus métastatique

A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer

Daizumoto, Kei ; Yoshimaru, Tetsuro ; Matsushita, Yosuke ; Fukawa, Tomoya ; Uehara, Hisaori ; Ono, Masaya ; Komatsu, Masato ; Kanayama, Hiro-omi ; Katagiri, Toyomasa

The p53 and EGFR pathways are frequently altered in bladder cancers, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31 bound mutp53/SP1 and enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic [...]

A partir de données issues du projet "The Cancer Genome Atlas" et portant sur 10 224 échantillons tumoraux prélevés sur des patients atteints d'un cancer (32 types différents), cette étude identifie dix classes sur une base uniquement moléculaire, indépendamment des localisations anatomiques à l'exception des cancers du sein "basal-like"

Pan-cancer molecular classes transcending tumor lineage across 32 cancer types, multiple data platforms, and over 10,000 cases

Creighton, Chad J. ; Chen, Fengju ; Zhang, Yiqun ; Gibbons, Don L. ; Deneen, Benjamin ; Kwiatkowski, David ; Ittmann, Michael

Purpose: The Cancer Genome Atlas data resources represent an opportunity to explore commonalities across cancer types involving multiple molecular levels, but tumor lineage and histology can represent a barrier in moving beyond differences related to cancer type. Experimental Design: On the basis of gene expression data, we classified 10224 cancers, representing 32 major types, into ten molecular-based "classes."  Molecular patterns representing tissue or histologic dominant effects [...]