A partir d'échantillons sanguins prélevés sur 231 patients pédiatriques atteints d'une leucémie lymphoblastique aiguë, puis menée in vitro, cette étude identifie un sous-groupe de patients caractérisés par la présence de translocations impliquant les gènes EP300 et CREBBP

Whole transcriptome sequencing identified a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

Qian, Maoxiang ; Zhang, Hui ; Kham, Shirley Kow-Yin ; Liu, Shuguang ; Jiang, Chuang ; Zhao, Xujie ; Lu, Yi ; Goodings, Charnise ; Lin, Ting-Nien ; Zhang, Ranran ; Moriyama, Takaya ; Yin, Zhaohong ; Li, Zhenhua ; Quah, Thuan Chong ; Ariffin, Hany ; Tan, Ah Moy ; Shen, Shuhong ; Bhojwani, Deepa ; Hu, Shaoyan ; Chen, Suning ; Zheng, Huyong ; Pui, Ching-Hon ; Yeoh, Allen Eng-Juh ; Yang, Jun J

Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through [...]

A partir d'échantillons tumoraux prélevés sur 50 patients atteints d'une tumeur germinale, cette étude identifie un ensemble d'anomalies génomiques caractéristiques de la tumeur primitive, puis d'autres anomalies associées à l'apparition d'une résistance à la chimiothérapie

Genomic evolution and chemoresistance in germ-cell tumours

Taylor-Weiner, Amaro ; Zack, Travis ; O’Donnell, Elizabeth ; Guerriero, Jennifer L. ; Bernard, Brandon ; Reddy, Anita ; Han, G. Celine ; Aldubayan, Saud ; Amin-Mansour, Ali ; Schumacher, Steven E. ; Litchfield, Kevin ; Turnbull, Clare ; Gabriel, Stacey ; Beroukhim, Rameen ; Getz, Gad ; Carter, Scott L. ; Hirsch, Michelle S. ; Letai, Anthony ; Sweeney, Christopher ; Van Allen, Eliezer M.

Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and [...]

Cet article passe en revue les travaux récents suggérant que les carcinomes séreux ovariens de haut grade, les carcinomes à cellules claires et les carcinomes endométrioïdes se développent à partir de tissus qui, normalement, ne sont pas présents dans un ovaire

The disparate origins of ovarian cancers: pathogenesis and prevention strategies

Karnezis, Anthony N. ; Cho, Kathleen R. ; Gilks, C. Blake ; Pearce, Celeste Leigh ; Huntsman, David G.

Ovarian cancer is the fifth cause of cancer-related death in women and comprises a histologically and genetically broad range of tumours, including those of epithelial, sex cord-stromal and germ cell origin. Recent evidence indicates that high-grade serous ovarian carcinoma, clear cell carcinoma and endometrioid carcinoma primarily arise from tissues that are not normally present in the ovary. These histogenetic pathways are informing risk-reduction strategies for the prevention of ovarian and [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par des cellules mésothéliales du péritoine dans les processus invasif et métastatique d'une tumeur de l'estomac

Mesothelial cells create a novel tissue niche that facilitates gastric cancer invasion

Tanaka, Masamitsu ; Kuriyama, Sei ; Itoh, Go ; Maeda, Daichi ; Goto, Akiteru ; Tamiya, Yutaro ; Yanagihara, Kazuyoshi ; Yashiro, Masakazu ; Aiba, Namiko

Peritoneal mesothelial cells (PMC) cover organ surfaces in the abdominal cavity. In this study, lineage tracing revealed that PMC guide cancer cell invasion in the gastric wall and in peritoneal metastatic lesions. Serosal PMC covering the stomach surface entered the gastric wall to create a novel niche that favored gastric cancer cell invasion. PMC infiltration was induced by incorporation of cancer cell-derived, Wnt3a-containing extracellular vesicles (EV). Infiltrated PMC in turn promoted [...]

Menée in vitro à l'aide d'un dispositif tridimensionnel, cette étude met en évidence des mécanismes par lesquels des macrophages favorisent le processus métastatique

Macrophage-secreted TNFalpha and TGFbeta1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways

Li, Ran ; Hebert, Jess D. ; Lee, Tara A. ; Xing, Hao ; Boussommier-Calleja, Alexandra ; Hynes, Richard O. ; Lauffenburger, Douglas A. ; Kamm, Roger D.

The ability of a cancer cell to migrate through the dense extracellular matrix (ECM) within and surrounding the solid tumor is a critical determinant of metastasis. Macrophages enhance invasion and metastasis in the tumor microenvironment but the basis for their effects are not fully understood. Using a microfluidic 3D cell migration assay, we found that the presence of macrophages enhanced the speed and persistence of cancer cell migration through a 3D extracellular matrix in a matrix [...]

Menée à l'aide de xénogreffes de cellules prélevées sur des patients atteints d'une leucémie lymphoblastique aiguë, cette étude identifie une sous-population cellulaire combinant des propriétés de dormance à long terme, de résistance thérapeutique et de cellules souches

Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

Ebinger, Sarah ; Özdemir, Erbey Ziya ; Ziegenhain, Christoph ; Tiedt, Sebastian ; Castro Alves, Catarina ; Grunert, Michaela ; Dworzak, Michael ; Lutz, Christoph ; Turati, Virginia A ; Enver, Tariq ; Horny, Hans-Peter ; Sotlar, Karl ; Parekh, Swati ; Spiekermann, Karsten ; Hiddemann, Wolfgang ; Schepers, Aloys ; Polzer, Bernhard ; Kirsch, Stefan ; Hoffmann, Martin ; Knapp, Bettina ; Hasenauer, Jan ; Pfeifer, Heike ; Panzer-Grümayer, Renate ; Enard, Wolfgang ; Gires, Olivier ; Jeremias, Irmela

Tumor relapse is associated with dismal prognosis, but responsible biological principles remain incompletely understood. To isolate and characterize relapse-inducing cells, we used genetic engineering and proliferation-sensitive dyes in patient-derived xenografts of acute lymphoblastic leukemia (ALL). We identified a rare subpopulation that resembled relapse-inducing cells with combined properties of long-term dormancy, treatment resistance, and stemness. Single-cell and bulk expression [...]

Menée sur des lignées cellulaires et à l'aide d'un modèle murin de neuroblastome, cette étude identifie des gènes et des voies de signalisation (CADM1, SPHK1, YAP/TAZ) impliqués dans le processus métastatique

A metastatic mouse model identifies genes that regulate neuroblastoma metastasis

Seong, Bo Kyung Alex ; Fathers, Kelly E. ; Hallett, Robin M. ; Yung, Christina K. ; Stein, Lincoln D. ; Mouaaz, Samar ; Kee, Lynn ; Hawkins, Cynthia ; Irwin, Meredith S. ; Kaplan, David R.

Metastatic relapse is the major cause of death in pediatric neuroblastoma (NB), where there remains a lack of therapies to target this stage of disease. To understand the molecular mechanisms mediating NB metastasis, we developed a mouse model using intracardiac injection and in vivo selection to isolate malignant cell subpopulations with a higher propensity for metastasis to bone and the central nervous system. Gene expression profiling revealed primary and metastatic cells as two distinct [...]

Menée sur des lignées cellulaires de cancer de l'ovaire et à l'aide de xénogreffes, cette étude met en évidence des mécanismes de nature métabolique par lesquels l'enzyme USP13 favorise la progression tumorale

Amplification of USP13 drives ovarian cancer metabolism

Han, Cecil ; Yang, Lifeng ; Choi, Hyun Ho ; Baddour, Joelle ; Achreja, Abhinav ; Liu, Yunhua ; Li, Yujing ; Li, Jiada ; Wan, Guohui ; Huang, Cheng ; Ji, Guang ; Zhang, Xinna ; Nagrath, Deepak ; Lu, Xiongbin

Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lequels la kinase NEK6 favorise la résistance à la castration d'une tumeur de la prostate

Castration resistance in prostate cancer is mediated by the kinase NEK6

Choudhury, Atish D. ; Schinzel, Anna C. ; Cotter, Maura B. ; Lis, Rosina T. ; Labella, Katherine ; Lock, Ying Jie ; Izzo, Francesca ; Guney, Isil ; Bowden, Michaela ; Li, Yvonne Y. ; Patel, Jinal ; Hartman, Emily ; Carr, Steven A. ; Schenone, Monica ; Jaffe, Jacob D. ; Kantoff, Philip W. ; Hammerman, Peter S. ; Hahn, William C.

In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we [...]