Cet article passe en revue les travaux récents sur le rôle des éléments transposables dans le développement d'un cancer, notamment des séquences d'ADN LINE-1 dont l'activité induit des insertions somatiques dans les génomes tumoraux

Transposable elements in cancer

Burns, Kathleen H.

Transposable elements give rise to interspersed repeats, sequences that comprise most of our genomes. These mobile DNAs have been historically underappreciated [mdash] both because they have been presumed to be unimportant, and because their high copy number and variability pose unique technical challenges. Neither impediment now seems steadfast. Interest in the human mobilome has never been greater, and methods enabling its study are maturing at a fast pace. This Review describes the activity [...]

Menée à l'aide d'échantillons tumoraux prélevés sur 346 patients atteints d'un cancer colorectal métastatique, cette étude met en évidence une association entre la présence de réarrangements des gènes ALK, ROS1 et NTRK (27 patients) et un pronostic défavorable

ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer

Pietrantonio, Filippo ; Di Nicolantonio, Federica ; Schrock, Alexa B. ; Lee, Jeeyun ; Tejpar, Sabine ; Sartore-Bianchi, Andrea ; Hechtman, Jaclyn F. ; Christiansen, Jason ; Novara, Luca ; Tebbutt, Niall ; Fucà, Giovanni ; Antoniotti, Carlotta ; Kim, Seung Tae ; Murphy, Danielle ; Berenato, Rosa ; Morano, Federica ; Sun, James ; Min, Bosun ; Stephens, Philip J. ; Chen, Marissa ; Cremolini, Chiara

Background: ALK, ROS1, and NTRK fusions occur in 0.2% to 2.4% of colorectal cancers. Pioneer cases of metastatic colorectal cancer (mCRC) patients bearing rearrangements who benefited from anti-ALK, ROS, and TrkA-B-C therapies have been reported previously. Here we aimed at characterizing the clinical and molecular landscape of ALK, ROS1, and NTRK rearranged mCRC. Methods: Clinical features and molecular characteristics of 27 mCRC patients bearing ALK, ROS1, and NTRK rearranged tumors were [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en induisant la formation de cellules initiatrices de tumeurs, la protéine SND1 favorise le développement et la progression d'un carcinome hépatocellulaire

Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma

Jariwala, Nidhi ; Rajasekaran, Devaraja ; Mendoza, Rachel G. ; Shen, Xue-Ning ; Siddiq, Ayesha ; Akiel, Maaged A. ; Robertson, Chadia L. ; Subler, Mark A. ; Windle, Jolene J. ; Fisher, Paul B. ; Sanyal, Arun J. ; Sarkar, Devanand

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor-initiating cells (TIC). Mechanistic investigations [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels le facteur de transcription FOXM1 favorise le développement d'une tumeur

FOXM1 in Cancer: Interactions and Vulnerabilities

Gartel, Andrei L.

FOXM1 is a transcription factor of the Forkhead family that is required for cell proliferation of normal cells. However, FOXM1 is repeatedly overexpressed in a variety of human cancers, and it has been implicated in all major hallmarks of cancer delineated by Hanahan and Weinberg. It has been postulated that the oncogenic potential of FOXM1 is determined by its capacity to transactivate target genes that are implicated in different phases of cancer development. However, FOXM1 may also play an [...]

Menée sur des lignées cellulaires et à l'aide d'échantillons de tissu tumoral et de tissu sain prélevés sur des patientes atteintes d'un cancer du sein triplement négatif, cette étude met en évidence des mécanismes par lesquels, en ciblant le gène SETBP1, le micro-ARN miR-211-5p exerce une fonction de suppresseur de tumeurs

MicroRNA-211-5p suppresses tumour cell proliferation, invasion, migration and metastasis in triple-negative breast cancer by directly targeting SETBP1

Chen, Liang-liang ; Zhang, Zhou-jing ; Yi, Zhan-bo ; Li, Jian-jun

Background: Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancer in women globally. This subtype often has early and high recurrence rates, resulting in poor survival, partially due to lack of targeted therapies. To date, the detailed molecular mechanisms underlying TNBC progression are unclear. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyse the expression and function of a metastasis-associated miRNA named miR-211-5p in TNBC. [...]

Menée à l'aide de modèles murins transgéniques, cette étude met en évidence des mécanismes par lesquels, en coopération avec la protéine issue d'un gène Hras présentant la mutation G12V, la protéine ATXN7 favorise la prolifération des cellules d'une tumeur de la thyroïde

Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene

Montero-Conde, Cristina ; Leandro-Garcia, Luis J. ; Chen, Xu ; Oler, Gisele ; Ruiz-Llorente, Sergio ; Ryder, Mabel ; Landa, Iñigo ; Sanchez-Vega, Francisco ; La, Konnor ; Ghossein, Ronald A. ; Bajorin, Dean F. ; Knauf, Jeffrey A. ; Riordan, Jesse D. ; Dupuy, Adam J. ; Fagin, James A.

Oncogenic RAS mutations are present in 15–30% of thyroid carcinomas. Endogenous expression of mutant Ras is insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. We used Sleeping Beauty (SB) transposon mutagenesis to identify events that cooperate with HrasG12V in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor [...]

Menée in vitro et in vivo sur des modèles de carcinome hépatocellulaire, cette étude met en évidence des mécanismes par lesquels, en se liant à la N-cadhérine exprimée par les cellules cancéreuses, le micro-ARN miR-199b-5p réprime une transition épithélio-mésenchymateuse

MicroRNA-199b-5p attenuates TGF-[beta]1-induced epithelial-mesenchymal transition in hepatocellular carcinoma

Zhou, Shao-jun ; Liu, Fu-yao ; Zhang, An-hong ; Liang, Hui-fang ; Wang, Ye ; Ma, Rong ; Jiang, Yuan-hui ; Sun, Nian-feng

Background: Accumulating evidence indicates that N-cadherin is a cell adhesion molecule that has critical roles in tumour progression. However, the role of N-cadherin in hepatocellular carcinoma (HCC) remains controversial. Methods: This study aims to investigate the expression status of N-cadherin and its molecular mechanisms in HCC. Results: The expression of N-cadherin was markedly overexpressed in HCC tissues and cell lines. We identified that miR-199b-5p binds to the 3′-UTR of N-cadherin [...]

Menée à l'aide de xénogreffes de lignées cellulaires de divers types de cancer (sein, prostate, mélanome, lymphome), cette étude met en évidence des mécanismes par lesquels l'expression de l'héparanase dans les lymphocytes NK régule les processus invasif et métastatique, ce qui incite notamment à mettre en garde contre une administration d'inhibiteurs de l'héparanase chez les patients atteints d'un cancer

NK cell heparanase controls tumor invasion and immune surveillance

Putz, Eva M. ; Mayfosh, Alyce J. ; Kos, Kevin ; Barkauskas, Deborah S. ; Nakamura, Kyohei ; Town, Liam ; Goodall, Katharine J. ; Yee, Dean Y. ; Poon, Ivan K. H. ; Baschuk, Nikola ; Souza-Fonseca-Guimaraes, Fernando ; Hulett, Mark D. ; Smyth, Mark J.

NK cells are highly efficient at preventing cancer metastasis but are infrequently found in the core of primary tumors. Here, have we demonstrated that freshly isolated mouse and human NK cells express low levels of the endo-β-D-glucuronidase heparanase that increase upon NK cell activation. Heparanase deficiency did not affect development, differentiation, or tissue localization of NK cells under steady-state conditions. However, mice lacking heparanase specifically in NK cells (Hpsefl/fl [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes de nature métabolique par lesquels une cycline dépendante des kinases, D3-CDK6, favorise la survie des cellules cancéreuses

The metabolic function of cyclin D3–CDK6 kinase in cancer cell survival

Wang, Haizhen ; Nicolay, Brandon N. ; Chick, Joel M. ; Gao, Xueliang ; Geng, Yan ; Ren, Hong ; Gao, Hui ; Yang, Guizhi ; Williams, Juliet A. ; Suski, Jan M. ; Keibler, Mark A. ; Sicinska, Ewa ; Gerdemann, Ulrike ; Haining, W. Nicholas ; Roberts, Thomas M. ; Polyak, Kornelia ; Gygi, Steven P. ; Dyson, Nicholas J. ; Sicinski, Piotr

D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results. Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3–CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the [...]

Menée à l'aide d'échantillons tumoraux prélevés sur 122 patients atteints d'un adénocarcinome métastatique du poumon, ainsi qu'à l'aide de données issues du projet "The Cancer Genome Atlas" et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en induisant une transition épithélio-mésenchymateuse, une surexpression de la protéine RCC2 favorise le processus métastatique

Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial-Mesenchymal Transition

Pang, Bo ; Wu, Nan ; Guan, Rongwei ; Pang, Lin ; Li, Xinlei ; Li, Su ; Tang, Liudi ; Guo, Ying ; Chen, Jialei ; Sun, Donglin ; Sun, Haiming ; Dai, Jialin ; Bai, Jing ; Ji, Guohua ; Liu, Peng ; Liu, An ; Wang, Qiushi ; Xiao, Sheng ; Fu, Songbin ; Jin, Yan

Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis. Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD. Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq [...]

Menée in vitro et in vivo sur des modèles de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels, en se liant au récepteur RAGE sur la surface des cellules cancéreuses, la protéase PR3 favorise la formation de métastases osseuses

Interaction between Tumor Cell Surface Receptor RAGE and Proteinase 3 Mediates Prostate Cancer Metastasis to Bone

Kolonin, Mikhail G. ; Sergeeva, Anna ; Staquicini, Daniela I. ; Smith, Tracey L. ; Tarleton, Christy A. ; Molldrem, Jeffrey J. ; Sidman, Richard L. ; Marchiò, Serena ; Pasqualini, Renata ; Arap, Wadih

Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels la localisation d'une tumeur et son environnement contraignent les effets des mutations oncogéniques sur le métabolisme des cellules tumorales

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

Mayers, Jared R. ; Vander Heiden, Matthew G.

Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids [...]