Menée à l'aide d'un modèle statistique et de données génomiques portant sur une cohorte d'environ 10 000 patients, cette étude démontre que de nombreuses mutations de "points chauds" de l'ADN tumoral sont en réalité passagères et surviennent de manière récurrente sans sélection positive sur des sites génomiques intrinsèquement mutables

Passenger Hotspot Mutations in Cancer

Hess, Julian M. ; Bernards, Andre ; Kim, Jaegil ; Miller, Mendy ; Taylor-Weiner, Amaro ; Haradhvala, Nicholas J. ; Lawrence, Michael S. ; Getz, Gad

Current statistical models for assessing hotspot significance do not properly account for variation in site-specific mutability, thereby yielding many false-positives. We thus (i) detail a Log-normal-Poisson (LNP) background model that accounts for this variability in a manner consistent with models of mutagenesis; (ii) use it to show that passenger hotspots arise from all common mutational processes; and (iii) apply it to a ∼10,000-patient cohort to nominate driver hotspots with far fewer [...]

Menée sur des lignées cellulaires d'adénocarcinome canalaire du pancréas et à l'aide d'un modèle murin, cette étude met en évidence le rôle de l'alpha-cétoglutarate dans la suppression tumorale induite par le facteur de transcription p53

α-Ketoglutarate links p53 to cell fate during tumour suppression

Morris, John P. ; Yashinskie, Jossie J. ; Koche, Richard ; Chandwani, Rohit ; Tian, Sha ; Chen, Chi-Chao ; Baslan, Timour ; Marinkovic, Zoran S. ; Sanchez-Rivera, Francisco J. ; Leach, Steven D. ; Carmona-Fontaine, Carlos ; Thompson, Craig B. ; Finley, Lydia W. S. ; Lowe, Scott W.

The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development2. Wild-type p53 is also known to modulate cellular metabolic pathways3, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell [...]

Menée à l'aide d'un modèle murin, de tissus humains sains ou tumoraux et de données du projet "The Cancer Genome Atlas ", cette étude analyse le profil d'expression du gène COMMD6, évalue l'association entre son expression et la survie des patients atteints d'un cancer, puis examine sa fonction biologique

Prognosis and modulation mechanisms of COMMD6 in human tumours based on expression profiling and comprehensive bioinformatics analysis

Yang, Mi ; Huang, Weiqiang ; Sun, Yaling ; Liang, Huazhen ; Chen, Min ; Wu, Xixi ; Wang, Xiaoqing ; Zhang, Longshan ; Cheng, Xiaoya ; Fan, Yao ; Pan, Hua ; Chen, Longhua ; Guan, Jian

Background : The Copper Metabolism MURR1 (COMM) domain family has been reported to play important roles in tumorigenesis. As a prototype for the COMMD family, the expression pattern and biological function of COMMD6 in human tumours remain unknown. Methods : COMMD6 expression in BALB/c mice and human tissues was examined using real-time PCR and immunohistochemistry. Kaplan–Meier analysis was applied to evaluate the prognosis of COMMD6 in tumours. Competing endogenous RNA (ceRNA) and [...]

Menée in vitro et à l'aide d'une modélisation, cette étude met en évidence l'intérêt d'évaluer les coûts énergétiques liés aux mécanismes de motilité cellulaire et aux contraintes spatiales de déplacement pour prédire les voies de migration des cellules cancéreuses

Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making

Zanotelli, Matthew R. ; Rahman-Zaman, Aniqua ; VanderBurgh, Jacob A. ; Taufalele, Paul V. ; Jain, Aadhar ; Erickson, David ; Bordeleau, Francois ; Reinhart-King, Cynthia A.

Cell migration during the invasion-metastasis cascade requires cancer cells to navigate a spatially complex microenvironment that presents directional choices to migrating cells. Here, we investigate cellular energetics during migration decision-making in confined spaces. Theoretical and experimental data show that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance as well as the degree of spatial confinement to direct [...]

Menée sur une lignée cellulaire de mélanome et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel les lymphocytes NK suppriment l'échappement immunitaire des cellules cancéreuses devenues résistantes aux lymphocytes T

Natural Killer Cells Suppress T Cell-Associated Tumor Immune Evasion

Freeman, Andrew J. ; Vervoort, Stephin J. ; Ramsbottom, Kelly M. ; Kelly, Madison J. ; Michie, Jessica ; Pijpers, Lizzy ; Johnstone, Ricky W. ; Kearney, Conor J. ; Oliaro, Jane

Despite the clinical success of cancer immunotherapies, the majority of patients fail to respond or develop resistance through disruption of pathways that promote neo-antigen presentation on MHC I molecules. Here, we conducted a series of unbiased, genome-wide CRISPR/Cas9 screens to identify genes that limit natural killer (NK) cell anti-tumor activity. We identified that genes associated with antigen presentation and/or interferon-? (IFN-?) signaling protect tumor cells from NK cell killing. [...]

Menée in vitro et à l'aide d'un modèle murin de tumeur mammaire, cette étude met en évidence un mécanisme par lequel l'inhibition de l'histone désacétylase 11 favorise le développement et la propagation des métastases ganglionnaires

Histone deacetylase 11 inhibition promotes breast cancer metastasis from lymph nodes

Leslie, Patrick L. ; Chao, Yvonne L. ; Tsai, Yi-Hsuan ; Ghosh, Subrata K. ; Porrello, Alessandro ; Van Swearingen, Amanda E. D. ; Harrison, Emily B. ; Cooley, Brian C. ; Parker, Joel S. ; Carey, Lisa A. ; Pecot, Chad V.

Lymph node (LN) metastases correspond with a worse prognosis in nearly all cancers, yet the occurrence of cancer spreading from LNs remains controversial. Additionally, the mechanisms explaining how cancers survive and exit LNs are largely unknown. Here, we show that breast cancer patients frequently have LN metastases that closely resemble distant metastases. In addition, using a microsurgical model, we show how LN metastasis development and dissemination is regulated by the expression of a [...]

Menée à l'aide d'un modèle murin de mélanome, cette étude démontre que l'hétérogénéité tumorale induite par les ultraviolets B réduit l'activité antitumorale des cellules du système immunitaire

UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

Wolf, Yochai ; Bartok, Osnat ; Patkar, Sushant ; Eli, Gitit Bar ; Cohen, Sapir ; Litchfield, Kevin ; Levy, Ronen ; Jiménez-Sánchez, Alejandro ; Trabish, Sophie ; Lee, Joo Sang ; Karathia, Hiren ; Barnea, Eilon ; Day, Chi-Ping ; Cinnamon, Einat ; Stein, Ilan ; Solomon, Adam ; Bitton, Lital ; Pérez-Guijarro, Eva ; Dubovik, Tania ; Shen-Orr, Shai S. ; Miller, Martin L. ; Merlino, Glenn ; Levin, Yishai ; Pikarsky, Eli ; Eisenbach, Lea ; Admon, Arie ; Swanton, Charles ; Ruppin, Eytan ; Samuels, Yardena

Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors [...]

Cet article passe en revue les caractéristiques du microenvironnement tumoral du carcinome rénal à cellules claires et analyse leur influence sur le pronostic et la réponse thérapeutique

Tumor Microenvironment Dynamics in Clear-Cell Renal Cell Carcinoma

Vuong, Lynda ; Kotecha, Ritesh R. ; Voss, Martin H. ; Hakimi, A. Ari

Renal cell carcinoma stands out as one of the most immune-infiltrated tumors in pan-cancer comparisons. Features of the tumor microenvironment heavily affect disease biology and may affect responses to systemic therapy. With evolving frontline options in the metastatic setting, several immune checkpoint blockade regimens have emerged as efficacious, and there is growing interest in characterizing features of tumor biology that can reproducibly prognosticate patients and/or predict the [...]

Menée à l'aide de 70 échantillons tumoraux prélevés sur des patients adultes atteints d'un gliome, cette étude démontre que les altérations transcriptionnelles dans ce type de tumeur résultent principalement de mécanismes non dépendants de la méthylation de l'ADN

Transcriptional alterations in glioma result primarily from DNA methylation–independent mechanisms

Court, Franck ; Le Boiteux, Elisa ; Fogli, Anne ; Müller-Barthélémy, Mélanie ; Vaurs-Barrière, Catherine ; Chautard, Emmanuel ; Pereira, Bruno ; Biau, Julian ; Kemeny, Jean-Louis ; Khalil, Toufic ; Karayan-Tapon, Lucie ; Verrelle, Pierre ; Arnaud, Philippe

In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. To dissect the relative contribution of DNA methylation–dependent and –independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type [...]