Menée in vitro à l'aide d'olaparib et de rucaparib, deux inhibiteurs de PARP, cette étude met en évidence des mécanismes par lesquels PARP1 favorise la formation de translocations chromosomiques dans les leucémies aiguës

PARP1 is required for chromosomal translocations

Wray, Justin ; Williamson, Elizabeth A. ; Singh, Sudha B. ; Wu, Yuehan ; Cogle, Christopher R. ; Weinstock, David M. ; Zhang, Yu ; Lee, Suk-Hee ; Zhou, Daohong ; Shao, Lijian ; Hauer-Jensen, Martin ; Pathak, Rupak ; Klimek, Virginia ; Nickoloff, Jac A. ; Hromas, Robert

Chromosomal translocations are common contributors to malignancy, yet little is known about the precise molecular mechanisms by which they are generated. Sequencing translocation junctions in acute leukemias revealed that the translocations were likely mediated by a DNA double-strand break (DSB) repair pathway termed non-homologous end joining (NHEJ). There are major two types of NHEJ, the more common classical pathway initiated by the Ku complex, and the alternative pathway initiated by PARP1. [...]

Cet article passe en revue les travaux récents sur le rôle de mutations du gène SF3B1 dans les leucémies lymphocytaires chroniques

SF3B1 mutations in chronic lymphocytic leukemia

Wan, Youzhong ; Wu, Catherine J.

SF3B1 is a critical component of the splicing machinery, which catalyzes the removal of introns from precursor mRNA. Next-generation sequencing studies have identified mutations in SF3B1 in chronic lymphocytic leukemia (CLL) at high frequency. In CLL, SF3B1 mutation is associated with more aggressive disease and shorter survival, and recent studies suggest that it can be incorporated into prognostic schema to improve the prediction of disease progression. Mutations in SF3B1 are predominantly [...]

Menée sur des cellules leucémiques de deux paires de jumeaux atteints d'une leucémie lymphoblastique aiguë, cette étude met en évidence l'enchaînement temporel des mutations somatiques

Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia

Ma, Yussanne ; Dobbins, Sara E. ; Sherborne, Amy L. ; Chubb, Daniel ; Galbiati, Marta ; Cazzaniga, Giovanni ; Micalizzi, Concetta ; Tearle, Rick ; Lloyd, Amy L. ; Hain, Richard ; Greaves, Mel ; Houlston, Richard S.

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal [...]

Cet article passe en revue les travaux récents sur les mécanismes biologiques des leucémies avec réarrangements du gène MLL

In focus: MLL-rearranged leukemia

de Boer, J. ; Walf-Vorderwulbecke, V. ; Williams, O.

The molecular mechanisms underlying oncogenesis in leukemias associated with rearrangement of the Mixed Lineage Leukemia (MLL) gene have received a considerable amount of attention over the last two decades. In this review we will focus on recent studies, published over the past year, that reveal new insights into the multi-protein complexes formed by MLL and MLL fusion proteins, the role of epigenetic deregulation in MLL fusion function, downstream transcriptional target genes, the importance [...]

A partir d'échantillons tumoraux prélevés sur 22 patientes atteintes d'un carcinome lobulaire invasif récidivant, cette étude montre que les tumeurs présentant une mutation du gène CDH1 sont associées à de fréquentes mutations du gène HER2

Relapsed classic E-cadherin (CDH1) mutated invasive lobular breast cancer demonstrates a high frequency of HER2 (ERBB2) gene mutations

Ross, Jeffrey S ; Wang, Kai ; Sheehan, Christine E ; Boguniewicz, Anne ; Otto, Geoff ; Downing, Sean R ; Curran, John ; Yelensky, Roman ; Lipson, Doron ; Palmer, Gary ; Sun, James ; Ali, Siraj ; He, Jie ; Miller, Vincent A. ; Stephens, Philip J.

Purpose: We queried whether comprehensive genomic profiling using a next generation sequencing (NGS)-based assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC). Experimental Design: DNA sequencing (Illumina HiSeq 2000) was performed for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization-captured libraries using DNA isolated from FFPE [...]

Menée sur des échantillons de néoplasie précoce, de tissu sain adjacent et de carcinome prélévés sur 6 patientes, cette étude analyse l'évolution du génome durant la progression vers un cancer du sein en dressant, pour chaque patiente, un arbre phylogénétique des mutations somatiques

Genome Evolution during Progression to Breast Cancer

Newburger, Daniel E ; Kashef-Haghighi, Dorna ; Weng, Ziming ; Salari, Raheleh ; Sweeney, Robert T ; Brunner, Alayne L ; Zhu, Shirley X ; Guo, Xiangqian ; Varma, Sushama ; Troxell, Megan L ; West, Robert B ; Batzoglou, Serafim ; Sidow, Arend

Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole genome sequencing of early [...]

Menée à partir de 151 échantillons tumoraux prélevés sur des patients pédiatriques atteints d'un gliome de bas grade et à l'aide de xénogreffes, cette étude met en évidence des anomalies génomiques fréquentes, notamment des duplications intragéniques d'une portion du gène FGFR1

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and [...]

Cet article passe en revue les travaux récents sur le rôle des cellules souches cancéreuses dans le cancer de l'estomac

Gastric cancer stem cells: A novel therapeutic target

Singh, Shree Ram

Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow–derived mesenchymal cells, [...]

A partir d'un modèle cellulaire à quatre étapes, cette étude montre que, lors de la transformation maligne, la majorité des gènes dont l'expression est modifiée subissent une régulation négative

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson, Frida ; Skogs, Marie ; Huss, Mikael ; Rexhepaj, Elton ; O’Hurley, Gillian ; Klevebring, Daniel ; Pontén, Fredrik ; Gad, Annica K. B. ; Uhlén, Mathias ; Lundberg, Emma

The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a four-stage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that ∼6% (n = 1,357) of the human protein-coding [...]

Menée à l'aide d'un modèle murin génétiquement modifié, cette étude met en évidence des mécanismes par lesquels, en régulant l'activation du gène SRC, deux facteurs induits par l'hypoxie, HIF1α et HIF2α, favorisent le processus métastatique d'un mélanome

HIF1α and HIF2α independently activate SRC to promote melanoma metastases

Hanna, Sara C. ; Krishnan, Bhavani ; Bailey, Sean T. ; Moschos, Stergios J. ; Kuan, Pei-Fen ; Shimamura, Takeshi ; Osborne, Lukas D. ; Siegel, Marni B. ; Duncan, Lyn M. ; x, ; Brien, E. Tim ; Superfine, Richard ; Miller, C. Ryan ; Simon, M. Celeste ; Wong, Kwok-Kin ; Kim, William Y.

Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIF) family of transcription factors is upregulated in melanoma by key oncogenic drivers. HIFs promote the activation of genes involved in cancer initiation, progression, and metastases. Hypoxia has been shown to enhance the invasiveness and metastatic potential of tumor cells by regulating the genes involved in the breakdown of the ECM as well as genes that control [...]

Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence le rôle joué par le récepteur du facteur de croissance des fibroblastes, FGFR1, dans le processus métastatique d'un cancer de la prostate

FGFR1 is Essential for Prostate Cancer Progression and Metastasis

Yang, Feng ; Zhang, Yongyou ; Ressler, Steven J. ; Ittmann, Michael M. ; Ayala, Gustavo E ; Dang, Truong D. ; Wang, Fen ; Rowley, David R

The fibroblast growth factor receptor FGFR1 is ectopically expressed in prostate carcinoma cells, but its functional contributions are undefined. In this study, we report the evalulation of a tissue-specific conditional deletion mutant generated in an ARR2PBi(Pbsn)-Cre/TRAMP/fgfr1loxP/loxP transgenic mouse model of prostate cancer. Mice lacking fgfr1 in prostate cells developed smaller tumors that also included distinct cancer foci still expressing fgfr1 indicating focal escape from gene [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la gankyrine dans la formation de métastases hépatiques d'un cancer colorectal

Gankyrin activates IL-8 to promote hepatic metastasis of colorectal cancer

Bai, Zhao-fang ; Tai, Yanhong ; Li, Weihua ; Zhen, Cheng ; Gu, Weiting ; Jian, Zhao ; Wang, Qianyi ; Lin, Jieru E. ; Zhao, Qing ; Gong, Weili ; Liang, Bing ; Wang, Chenguang ; Zhou, Tao

Hepatic metastasis is responsible for the majority of colorectal cancer (CRC)-related mortalities. Although Gankyrin (PSMD10) has been implicated in cancer metastasis, its exact role and underlying mechanisms of CRC hepatic metastasis remain largely unknown. Herein, we demonstrated that the expression of Gankyrin was higher in primary CRC with hepatic metastasis compared to CRC without metastasis. RNAi-mediated silencing of Gankyrin expression in highly metastatic human CRC cells impaired their [...]

Cet article passe en revue les perspectives offertes par l'imagerie en bioluminescence et les modèles murins génétiquement modifiés pour étuder la biologie des tumeurs et la réponse thérapeutique in vivo

Illuminating Cancer Systems with Genetically Engineered Mouse Models and Coupled Luciferase Reporters In Vivo

Kocher, Brandon ; Piwnica-Worms, David

Bioluminescent imaging (BLI) is a powerful noninvasive tool that has dramatically accelerated the in vivo interrogation of cancer systems and longitudinal analysis of mouse models of cancer over the past decade. Various luciferase enzymes have been genetically engineered into mouse models (GEMM) of cancer, which permit investigation of cellular and molecular events associated with oncogenic transcription, posttranslational processing, protein–protein interactions, transformation, and oncogene [...]

Cet article passe en revue l'intérêt des expériences cellulaires menées en condition de micro-gravité pour la compréhension de mécanismes liés au cancer

Using space-based investigations to inform cancer research on Earth

Becker, Jeanne L. ; Souza, Glauco R.

Experiments conducted in the microgravity environment of space are not typically at the forefront of the mind of a cancer biologist. However, space provides physical conditions that are not achievable on Earth, as well as conditions that can be exploited to study mechanisms and pathways that control cell growth and function. Over the past four decades, studies have shown how exposure to microgravity alters biological processes that may be relevant to cancer. In this Review, we explore the [...]

Menée à l'aide d'un modèle murin de cancer du poumon induit par le gène Kras, cette étude présente un modèle mathématique et statistique rendant compte de l'existence d'une population cellulaire à faible taux de renouvellement dans les tumeurs

Mathematical modeling of tumor cell proliferation kinetics and label retention in a mouse model of lung cancer

Zheng, Yanyan ; Moore, Helen ; Piryatinska, Alexandra ; Solis, Trinidad ; Sweet-Cordero, E. Alejandro

Slowly-cycling tumor cells that may be present in human tumors may evade cytotoxic therapies, which tend to be more efficient at destroying cells with faster growth rates. However, the proportion and growth rate of slowly-cycling tumor cells is often unknown in preclinical model systems used for drug discovery. Here we report a quantitative approach to quantitate slowly-cycling malignant cells in solid tumors, using a well-established mouse model of Kras-induced lung cancer (KrasG12D/+). [...]