Menée initialement sur deux patientes pédiatriques jumelles monozygotes dont l'une est atteinte d'une leucémie aiguë, puis sur une cohorte complémentaire de 241 patients, cette étude met en évidence le rôle joué des mutations du gène SETD2, codant pour une méthyltransférase, dans le développement de la maladie

Identification of functional cooperative mutations of SETD2 in human acute leukemia

Zhu, Xiaofan ; He, Fuhong ; Zeng, Huimin ; Ling, Shaoping ; Chen, Aili ; Wang, Yaqin ; Yan, Xiaomei ; Wei, Wei ; Pang, Yakun ; Cheng, Hui ; Hua, Chunlan ; Zhang, Yue ; Yang, Xuejing ; Lu, Xin ; Cao, Lihua ; Hao, Lingtong ; Dong, Lili ; Zou, Wei ; Wu, Jun ; Li, Xia ; Zheng, Si ; Yan, Jin ; Zhou, Jing ; Zhang, Lixia ; Mi, Shuangli ; Wang, Xiaojuan ; Zhang, Li ; Zou, Yao ; Chen, Yumei ; Geng, Zhe ; Wang, Jianmin ; Zhou, Jianfeng ; Liu, Xin ; Wang, Jianxiang ; Yuan, Weiping ; Huang, Gang ; Cheng, Tao ; Wang, Qian-fei

Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene–rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene3 and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 [...]

Menée à l'aide de techniques de séquençage de prochaine génération sur des échantillons prélevés sur 309 patients atteints d'une leucémie lymphocytaire chronique récemment diagnostiquée, cette étude identifie la présence de petites populations sous-clonales présentant des mutations du gène TP53 et met en évidence leur association avec un pronostic défavorable

Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia

Rossi, Davide ; Khiabanian, Hossein ; Spina, Valeria ; Ciardullo, Carmela ; Bruscaggin, Alessio ; Famà, Rosella ; Rasi, Silvia ; Monti, Sara ; Deambrogi, Clara ; De Paoli, Lorenzo ; Wang, Jiguang ; Gattei, Valter ; Guarini, Anna ; Foà, Robin ; Rabadan, Raul ; Gaidano, Gianluca

TP53 mutations are strong predictors of poor survival and refractoriness in chronic lymphocytic leukemia (CLL) and have direct implications for disease management. Clinical information on TP53 mutations is limited to lesions represented in >20% leukemic cells. Here we tested the clinical impact and prediction of chemorefractoriness of very small TP53 mutated subclones. The TP53 gene underwent ultra-deep-next generation sequencing (NGS) in 309 newly diagnosed CLL. A robust bioinformatic [...]

Menée initialement sur une cohorte de 11 patients atteints d'un lymphome T cutané, puis sur une cohorte complémentaire de 42 patients, cette étude identifie des mutations du gène PLCG1 associées à la prolifération des cellules cancéreuses

PLCG1 mutations in cutaneous T-cell lymphomas

Vaqué, José P. ; Gómez-López, Gonzalo ; Monsálvez, Verónica ; Varela, Ignacio ; Martinez, Nerea ; Pérez, Cristina ; Dominguez, Orlando ; Graña, Osvaldo ; Rodríguez-Peralto, José L. ; Rodríguez-Pinilla, Socorro M. ; González-Vela, Carmen ; Rubio-Camarillo, Miriam ; Martín-Sánchez, Esperanza ; Pisano, David G. ; Papadavid, Evangelia ; Papadaki, Theodora ; Requena, Luis ; Garcia-Marco, Jose A. ; Méndez, Miriam ; Provencio, Mariano ; Hospital, Mercedes ; Suárez-Massa, Dolores ; Postigo, Concepción ; San Segundo, David ; López-Hoyos, Marcos ; Ortiz-Romero, Pablo L. ; Piris, Miguel A. ; Sanchez-Beato, Margarita

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, and whose aggressive forms lack effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCR). DNAs from 11 CTCL patients, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection [...]

Menée par une technique de séquençage du génome entier sur 5 échantillons de métastases prélevés chez un patient atteint d'un mélanome, cette étude identifie la présence de mutations associées à la résistance à un inhibiteur de BRAF

Whole genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition

Turajlic, S. ; Furney, S. J. ; Stamp, G. ; Rana, S. ; Ricken, G. ; Oduko, Y. ; Saturno, G. ; Springer, C. ; Hayes, A. ; Gore, M. ; Larkin, J. ; Marais, R.

Background. BRAF is mutated in ∼42% of human melanomas [1] and pharmacological BRAF inhibitors such as vemurafenib and dabrafenib achieve dramatic responses in patients whose tumours harbour BRAFV600 mutations [2-5]. Objective responses occur in ∼50% of patients and disease stabilisation in a further ∼30%, but ∼20% of patients present primary or innate resistance and do not respond. Here we investigated the underlying cause of treatment failure in a patient with BRAF mutant melanoma who [...]

Cet article passe en revue les travaux récents sur les cinq gènes suppresseurs de tumeurs ING, impliqués dans la régulation de la prolifération cellulaire et des mécanismes d'apoptose ou de sénescence

The ING tumor suppressor genes: Status in human tumors

Guérillon, Claire ; Bigot, Nicolas ; Pedeux, Rémy

ING genes (ING1–5) were identified has tumor suppressor genes. ING proteins are characterized as Type II TSGs since they are involved in the control of cell proliferation, apoptosis and senescence. They may also function as Type I TSGs since they are also involved in DNA replication and repair. Most studies have reported that they are frequently lost in human tumors and epigenetic mechanisms or misregulation of their transcription may be involved. Recently, studies have described that this loss [...]

Menée à l'aide d'un modèle murin de cancer du poumon non à petites cellules lié à la mutation G12D du gène Kras, cette étude met en évidence des mécanismes tumorigéniques différents en fonction de l'absence d'expression du gène Notch1 ou du gène Notch2

Opposing role of Notch1 and Notch2 in a KrasG12D-driven murine non-small cell lung cancer model

Baumgart, A. ; Mazur, P. K. ; Anton, M. ; Rudelius, M. ; Schwamborn, K. ; Feuchtinger, A. ; Behnke, K. ; Walch, A. ; Braren, R. ; Peschel, C. ; Duyster, J. ; Siveke, J. T. ; Dechow, T.

Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a KrasG12D-driven endogenous NSCLC mouse model, we analyzed the effect of [...]

Menée in vitro, in vivo et à partir de données issues du projet "The Cancer Genome Atlas", cette étude met en évidence des mécanismes par lesquels, en inhibant la signalisation NF-κB, l'alpha-caténine joue un rôle de suppresseur de tumeurs dans les cancers du sein "basal-like" n'exprimant pas l'E-cadhérine

α-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-κB signalling

Piao, Hai-long ; Yuan, Yuan ; Wang, Min ; Sun, Yutong ; Liang, Han ; Ma, Li

Basal-like breast cancer is a highly aggressive tumour subtype associated with poor prognosis. Aberrant activation of NF-κB signalling is frequently found in triple-negative basal-like breast cancer cells, but the cause of this activation has remained elusive.Here we report that α-catenin functions as a tumour suppressor in E-cadherin-negative basal-like breast cancer cells by inhibiting NF-κB signalling. Mechanistically, α-catenin interacts with the IκBα protein, and stabilizes IκBα by [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en activant la signalisation Notch1, la protéine EZH2 favorise la prolifération des cellules souches de cancer du sein triplement négatif

EZH2 expands breast stem cells through activation of NOTCH1 signaling

Gonzalez, Maria E. ; Moore, Heather M. ; Li, Xin ; Toy, Kathy A. ; Huang, Wei ; Sabel, Michael S. ; Kidwell, Kelley M. ; Kleer, Celina G.

Breast cancer is the second-leading cause of cancer-related deaths in women, but the details of how it begins remain elusive. Increasing evidence supports the association of aggressive triple-negative (TN) breast cancer with heightened expression of the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) and increased tumor-initiating cells (TICs). However, mechanistic links between EZH2 and TICs are unclear, and direct demonstration of a tumorigenic function of EZH2 in vivo is lacking. [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la protéine ICAT régule la motilité des cellules métastatiques de mélanome

ICAT, Inhibitor of β-catenin and TCF4, a new modulator of melanoma cells motility and invasiveness

Domingues, Melanie J ; Rambow, Florian ; Job, Bastien ; Papon, Laura ; Liu, Wanguo ; Larue, Lionel ; Bonaventure, Jacky

ICAT (inhibitor of β-catenin and TCF-4) negatively regulates β-catenin co-transcriptional activity by competing with LEF/TCF factors. Deregulation of β-catenin signaling is frequently implicated in melanoma, a highly invasive skin cancer. We observed that high ICAT levels in a panel of human melanoma cell lines correlated with their capacity to form metastases in nude mice. To address the role of ICAT in melanoma, we ectopically expressed ICAT in metastatic and non-metastatic melanoma cell [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par les cellules alvéolaires de type II dans le développement d'un cancer du poumon

Alveolar progenitor and stem cells in lung development, renewal and cancer

Desai, Tushar J. ; Brownfield, Douglas G. ; Krasnow, Mark A.

Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la cofiline, une protéine impliquée dans la réorganisation du cytosquelette, favorise les processus invasif et métastatique d'un cancer de la prostate

Cofilin Drives Cell Invasive and Metastatic Responses to TGF-β in Prostate Cancer

Collazo, Joanne ; Zhu, Beibei ; Larkin, Spencer ; Horbinski, Craig ; Pu, Hong ; Martin, Sarah K ; Koochekpour, Shahriar ; Kyprianou, Natasha

Cofilin (CFL) is an F-actin severing protein required for the cytoskeleton reorganization and filopodia formation, which drives cell migration. CFL binding and severing of F-actin is controlled by Ser3 phosphorylation, but the contributions of this step to cell migration during invasion and metastasis of cancer cells are unclear. In this study we addressed the question in prostate cancer cells, including the response to TGF-β, a critical regulator of migration. In cells expressing wild-type [...]

Menée in vitro, sur une cohorte initiale de 111 patients atteints d'un cancer colorectal, puis sur des données complémentaires portant sur 217 patients inclus dans le projet "The Cancer Genome Atlas", cette étude met en évidence des mécanismes par lesquels le micro-ARN miR-200 régule la transition épithélio-mésenchymateuse, puis identifie une association entre une faible expression du micro-ARN miR-200 et un pronostic défavorable

MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients

Pichler, M. ; Ress, A. L. ; Winter, E. ; Stiegelbauer, V. ; Karbiener, M. ; Schwarzenbacher, D. ; Scheideler, M. ; Ivan, C. ; Jahn, S. W. ; Kiesslich, T. ; Gerger, A. ; Bauernhofer, T. ; Calin, G. A. ; Hoefler, G.

Background: MicroRNAs (miRNAs) regulate the biological properties of colorectal cancer (CRC) cells and might serve as potential prognostic factors and therapeutic targets. In this study, we therefore globally profiled miRNAs associated with E-cadherin expression in CRC cells in an attempt to identify miRNAs that are associated with aggressive clinical course in CRC patients. Methods: Two CRC cell lines (Caco-2 and HRT-18) with different E-cadherin expression pattern were profiled for [...]

Menée sur des lignées cellulaires de cancer du sein, cette étude met en évidence des mécanismes par lesquels, via la régulation de la signalisation KLF17/ID-1, la protéine DJ-1 favorise la transition épithélio-mésenchymateuse

DJ-1 upregulates breast cancer cell invasion by repressing KLF17 expression

Ismail, I. A. ; Kang, H. S. ; Lee, H. J. ; Kim, J. K. ; Hong, S. H.

Background: DJ-1 (PARK7) was reported as an oncogene in a Ras-dependent manner. Recent studies have shown that DJ-1 stimulates cell proliferation, cell invasion, and cancer metastasis. However, the molecular mehchanism by which DJ-1 induces cancer cell invasion and metastasis remains unclear. Methods: Breast cancer cells were transfected with DJ-1 siRNA or DJ-1 overexpression to investigate the effect of DJ-1 on KLF17 expression. ID-1 luciferase promoter assay was performed to evaluate [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, dans les cancers du sein présentant des mutations du gène TP53, la protéine Myo10 favorise les processus invasif et métastatique

Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis

Arjonen, Antti ; Kaukonen, Riina ; Mattila, Elina ; Rouhi, Pegah ; xF, ; gn, ; xE, ; s, Gunilla ; Sihto, Harri ; Miller, Bryan W. ; Morton, Jennifer P. ; Bucher, Elmar ; Taimen, Pekka ; Virtakoivu, Reetta ; Cao, Yihai ; Sansom, Owen J. ; Joensuu, Heikki ; Ivaska, Johanna

Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53–driven cancer invasion. Analysis of gene expression profiles from 2 breast [...]

Menée à partir d'échantillons tumoraux prélevés sur 3 patients atteints d'une tumeur stromale gastro-intestinale (GIST), cette étude décrit les caractéristiques du premier modèle murin orthotopique de GIST utilisant des tissus tumoraux humains

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor

Sicklick, Jason ; Leonard, Stephanie ; Babicky, Michele ; Tang, Chih-Min ; Mose, Evangeline ; French, Randall ; Jaquish, Dawn ; Hoh, Carl ; Peterson, Michael ; Schwab, Richard ; Lowy, Andrew

BACKGROUND:Gastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We [...]