Cet article passe en revue les travaux récents sur les mécanismes permettant de rendre compte de l'hétérogénéité temporelle et spatiale des tumeurs

Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine

Hiley, Crispin ; de Bruin, Elza ; McGranahan, Nicholas ; Swanton, Charles

The presence of multiple subclones within tumors mandates understanding of longitudinal and spatial subclonal dynamics. Resolving the spatial and temporal heterogeneity of subclones with cancer driver events may offer insight into therapy response, tumor evolutionary histories and clinical trial design.

Menée à l'aide d'un modèle murin permettant d'induire de façon sélective une instabilité chromosomique dans les lymphocytes T, cette étude met en évidence le développement rapide d'un lymphome lymphoblastique aigu et une aneuploïdie importante des cellules tumorales

Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress

Foijer, Floris ; Xie, Stephanie Z. ; Simon, Judith E. ; Bakker, Petra L. ; Conte, Nathalie ; Davis, Stephanie H. ; Kregel, Eva ; Jonkers, Jos ; Bradley, Allan ; Sorger, Peter K.

Aneuploidy is a hallmark of human solid cancers that arises from errors in mitosis and results in gain and loss of oncogenes and tumor suppressors. Aneuploidy poses a growth disadvantage for cells grown in vitro, suggesting that cancer cells adapt to this burden. To understand better the consequences of aneuploidy in a rapidly proliferating adult tissue, we engineered a mouse in which chromosome instability was selectively induced in T cells. A flanked by Lox mutation was introduced into the [...]

Menée sur des échantillons tumoraux prélevés sur 136 patients chinois atteints d'un lymphome diffus à grandes cellules B, cette étude identifie un ensemble de mutations somatiques, notamment d'un gène de la voie de signalisation Notch (DTX1)

Exome sequencing reveals novel mutation targets in diffuse large B cell lymphomas derived from Chinese patients

de Miranda, Noel F.C.C. ; Georgiou, Konstantinos ; Chen, Longyun ; Wu, Chenglin ; Gao, Zhibo ; Zaravinos, Apostolos ; Lisboa, Susana ; Enblad, Gunilla ; Teixeira, Manuel R. ; Zeng, Yixin ; Peng, Roujun ; Pan-Hammarström, Qiang

Next generation sequencing studies on diffuse large B cell lymphomas (DLBCL) have revealed novel targets of genetic aberrations but also high inter-cohort heterogeneity. Previous studies have suggested that the prevalence of disease sub-groups and cytogenetic profiles differ between Western and Asian patients. In order to characterize the coding genome of Chinese DLBCL, we performed whole-exome sequencing of DNA derived from 31 tumors and respective peripheral blood samples. The mutation [...]

Menée sur 69 paires d'échantillons de tumeurs primitives et de métastases prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence un fort degré de similarité entre les profils de mutations de 230 gènes, notamment KRAS, NRAS et BRAF, dans les tumeurs primitives et dans les métastases

Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions

Brannon, Angela ; Vakiani, Efsevia ; Sylvester, Brooke ; Scott, Sasinya ; McDermott, Gregory ; Shah, Ronak ; Kania, Krishan ; Viale, Agnes ; Oschwald, Dayna ; Vacic, Vladimir ; Emde, Anne-Katrin ; Cercek, Andrea ; Yaeger, Rona ; Kemeny, Nancy ; Saltz, Leonard ; Shia, Jinru ; D'Angelica, Michael ; Weiser, Martin ; Solit, David ; Berger, Michael

Background : Colorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of response to anti-EGFR therapy has become standard practice in the treatment of metastatic colorectal cancer; however, the quantity and type of tissue available for testing is frequently limited. Further, the degree to which the primary tumor is a faithful representation of metastatic disease [...]

Menée sur 4 échantillons tumoraux prélevés sur un patient présentant une mutation constitutionnelle du gène VHL et atteint d'un carcinome rénal à cellules claires, cette étude met notamment en évidence l'indépendance clonale des tumeurs

Development of synchronous VHL syndrome tumours reveals contingencies and constraints to tumour evolution

Fisher, Rosalie ; Horswell, Stuart ; Rowan, Andrew ; Salm, Max ; de Bruin, Elza ; Gulati, Sakshi ; McGranahan, Nicholas ; Stares, Mark ; Gerlinger, Marco ; Varela, Ignacio ; Crockford, Andrew ; Favero, Francesco ; Quidville, Virginie ; Andre, Fabrice ; Navas, Carolina ; Grönroos, Eva ; Nicol, David ; Hazell, Steve ; Hrouda, David ; O'Brien, Tim ; Matthews, Nik ; Phillimore, Ben ; Begum, Sharmin ; Rabinowitz, Adam ; Biggs, Jennifer ; Bates, Paul ; McDonald, Neil ; Stamp, Gordon ; Spencer-Dene, Bradley ; Hsieh, James ; Xu, Jianing ; Pickering, Lisa ; Gore, Martin ; Larkin, James ; Swanton, Charles

Background : Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. Results : We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la kinase ERK5 dans la croissance tumorale d'un carcinome hépatocellulaire

The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma

Rovida, Elisabetta ; Di Maira, Giovanni ; Tusa, Ignazia ; Cannito, Stefania ; Paternostro, Claudia ; Navari, Nadia ; Vivoli, Elisa ; Deng, Xianming ; Gray, Nathanael S ; Esparís-Ogando, Azucena ; David, Ezio ; Pandiella, Atanasio ; Dello Sbarba, Persio ; Parola, Maurizio ; Marra, Fabio

Objective : The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The ERK5 gene may be amplified in hepatocellular carcinoma (HCC), but its biological role has not been clarified. In this study, we explored the role of ERK5 expression and activity in HCC in vitro and in vivo. Design : ERK5 expression was evaluated in human liver tissue. Cultured HepG2 and Huh-7 were studied after ERK5 knockdown by siRNA or in the presence of the specific pharmacological [...]

Menée à l'aide de modèles murins et d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence des mécanismes par lesquels l'expression du récepteur EGFR dans des macrophages hépatiques favorise la prolifération des cellules tumorales

EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation

Lanaya, Hanane ; Natarajan, Anuradha ; Komposch, Karin ; Li, Liang ; Amberg, Nicole ; Chen, Lei ; Wculek, Stefanie K. ; Hammer, Martina ; Zenz, Rainer ; Peck-Radosavljevic, Markus ; Sieghart, Wolfgang ; Trauner, Michael ; Wang, Hongyang ; Sibilia, Maria

Hepatocellular carcinoma (HCC) is a frequent cancer with limited treatment options and poor prognosis. Tumorigenesis has been linked with macrophage-mediated chronic inflammation and diverse signalling pathways, including the epidermal growth factor receptor (EGFR) pathway. The precise role of EGFR in HCC is unknown, and EGFR inhibitors have shown disappointing clinical results. Here we discover that EGFR is expressed in liver macrophages in both human HCC and in a mouse HCC model. Mice lacking [...]

Cet article passe en revue les travaux récents sur les mécanismes de régulation des micro-ARNs associés à des mutations de gènes codant des enzymes Dicer

DICER1: mutations, microRNAs and mechanisms

Foulkes, William D. ; Priest, John R. ; Duchaine, Thomas F.

Dicer is central to microRNA-mediated silencing and several other RNA interference phenomena that are profoundly embedded in cancer gene networks. Most recently, both germline and somatic mutations in DICER1 have been identified in diverse types of cancer. Although some of the mutations clearly reduce the dosage of this key enzyme, others dictate surprisingly specific changes in select classes of small RNAs. This Review reflects on the molecular properties of the Dicer enzymes in small RNA [...]

Menée in vitro et à l'aide d'un modèle murin transgénique, cette étude met en évidence le rôle joué par la bêta-caténine dans le développement d'une tumeur du poumon présentant une mutation du gène EGFR

Bêta-catenin contributes to lung tumor development induced by EGFR mutations

Nakayama, Sohei ; Sng, Natasha ; Carretero, Julian ; Welner, Robert ; Hayashi, Yuichiro ; Yamamoto, Mihoko ; Tan, Alistair J. ; Yamaguchi, Norihiro ; Yasuda, Hiroyuki ; Li, Danan ; Soejima, Kenzo ; Soo, Ross A ; Costa, Daniel B. ; Wong, Kwok-Kin ; Kobayashi, Susumu S.

The discovery of somatic mutations in epidermal growth factor receptor (EGFR) and development of EGFR tyrosine kinase inhibitors (TKIs) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here we show that β-catenin is essential for development of EGFR mutated lung cancers. β-catenin was upregulated and activated in EGFR mutated cells. Mutant EGFR preferentially bound to and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en induisant l'expression de l'e-cadhérine, la phospholipase Cdelta1 exerce une fonction de suppresseur de tumeurs dans le cancer colorectal

Phospholipase Cdelta1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells

Satow, Reiko ; Hirano, Tamaki ; Batori, Ryosuke ; Nakamura, Tomomi ; Murayama, Yumi ; Fukami, Kiyoko

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CRC predict the ineffectiveness of EGF receptor-targeted therapy. Previous transcriptional microarray analysis suggests the association between phospholipase Cδ1 (PLCδ1) expression and KRAS mutation status in CRC. However, both the roles and the regulatory mechanisms of PLCδ1 in CRC are not known. Here, we found that the expression of [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels la surexpression de la protéine CIP4 favorise le processus métastatique d'un cancer du poumon non à petites cellules

CIP4 promotes lung adenocarcinoma metastasis and is associated with poor prognosis

Truesdell, P. ; Ahn, J. ; Chander, H. ; Meens, J. ; Watt, K. ; Yang, X. ; Craig, A. W. B.

Aberrant epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer (NSCLC) is linked to tumor progression, metastasis and poor survival rates. Here we report the role of Cdc42-interacting protein 4 (CIP4) in the regulation of NSCLC cell invasiveness and tumor metastasis. CIP4 was highly expressed in a panel of NSCLC cell lines and normal lung epithelial cell lines. Stable knockdown (KD) of CIP4 in lung adenocarcinoma H1299 cells, expressing wild-type EGFR, led to increased [...]

Menée à l'aide de xénogreffes de tumeurs de la prostate, cette étude met en évidence des mécanismes par lesquels la surexpression du canal calcique TRPV6 favorise la prolifération des cellules cancéreuses

TRPV6 calcium channel translocates to the plasma membrane via Orai1-mediated mechanism and controls cancer cell survival

Raphaël, Maylis ; Lehen’kyi, V’yacheslav ; Vandenberghe, Matthieu ; Beck, Benjamin ; Khalimonchyk, Sergiy ; Vanden Abeele, Fabien ; Farsetti, Leonardo ; Germain, Emmanuelle ; Bokhobza, Alexandre ; Mihalache, Adriana ; Gosset, Pierre ; Romanin, Christoph ; Clezardin, Philippe ; Skryma, Roman ; Prevarskaya, Natalia

Transient receptor potential vanilloid subfamily member 6 (TRPV6) is a highly selective calcium channel that has been considered as a part of store-operated calcium entry (SOCE). Despite its first discovery in the early 2000s, the role of this channel in prostate cancer (PCa) remained, until now, obscure. Here we show that TRPV6 mediates calcium entry, which is highly increased in PCa due to the remodeling mechanism involving the translocation of the TRPV6 channel to the plasma membrane via the [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels l'enzyme PARP-1 régule la transition épithélio-mésenchymateuse dans une tumeur de la prostate

PARP-1 Regulates Epithelial-Mesenchymal-Transition (EMT) in Prostate Tumorigenesis

Pu, Hong ; Horbinski, Craig ; Hensley, Patrick J. ; Matuszak, Emily A. ; Atkinson, Timothy ; Kyprianou, Natasha

Poly (ADP-ribose) polymerase (PARP) is involved in key cellular processes such as DNA replication and repair, gene transcription, cell proliferation and apoptosis. The role of PARP-1 in prostate cancer development and progression is not fully understood. The present study investigated the function of PARP-1 in prostate growth and tumorigenesis in vivo. Functional inactivation of PARP-1 by gene targeted deletion led to a significant reduction in the prostate gland size in young PARP-1-/- mice [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par le micro-ARN miR-182 dans le processus métastatique des sarcomes

MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes

Sachdeva, Mohit ; Mito, Jeffrey K. ; Lee, Chang-Lung ; Zhang, Minsi ; Li, Zhizhong ; Dodd, Rebecca D. ; Cason, David ; Luo, Lixia ; Ma, Yan ; Van Mater, David ; Gladdy, Rebecca ; Lev, Dina C. ; Cardona, Diana M. ; Kirsch, David G.

Metastasis causes most cancer deaths, but is incompletely understood. MicroRNAs can regulate metastasis, but it is not known whether a single miRNA can regulate metastasis in primary cancer models in vivo. We compared the expression of miRNAs in metastatic and nonmetastatic primary mouse sarcomas and found that microRNA-182 (miR-182) was markedly overexpressed in some tumors that metastasized to the lungs. By utilizing genetically engineered mice with either deletion of or overexpression of [...]

Cet article passe en revue les perspectives offertes par les technologies permettant le séquençage du génome à l'échelle d'une seule cellule pour la compréhension de la biologie des cancers

Cancer genomics: one cell at a time

Navin, Nicholas

The study of single cancer cells has transformed from qualitative microscopic images to quantitative genomic datasets. This paradigm shift has been fueled by the development of single-cell sequencing technologies, which provide a powerful new approach to study complex biological processes in human cancers.

Cet article passe en revue les travaux récents sur les mécanismes biologiques associés à la survenue d'un cancer du sein chez les jeunes patientes

Biology of breast cancer in young women

Azim, Hatem ; Partridge, Ann

Breast cancer arising at a young age is relatively uncommon, particularly in the developed world. Several studies have demonstrated that younger patients often experience a more aggressive disease course and have poorer outcome compared to older women. Expression of key biomarkers, including endocrine receptors, HER2 and proliferation markers, appears to be different in younger patients and young women are more likely to harbor a genetic predisposition. Despite these differences, little [...]