Cet article passe en revue les travaux récents sur le rôle joué dans la tumorigenèse par des mutations identifiées dans des régions non codantes du génome

The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations

Diederichs, Sven ; Bartsch, Lorenz ; Berkmann, Julia C. ; Fröse, Karin ; Heitmann, Jana ; Hoppe, Caroline ; Iggena, Deetje ; Jazmati, Danny ; Karschnia, Philipp ; Linsenmeier, Miriam ; Maulhardt, Thomas ; Möhrmann, Lino ; Morstein, Johannes ; Paffenholz, Stella V. ; Röpenack, Paula ; Rückert, Timo ; Sandig, Ludger ; Schell, Maximilian ; Steinmann, Anna ; Voss, Gjendine ; Wasmuth, Jacqueline ; Weinberger, Maria E. ; Wullenkord, Ramona

Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor-specific mutations not only in protein-coding sequences but also in non-coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy-driving mutations can occur in all genetic [...]

Menée à l'aide d'une technique de séquençage à haut débit sur 215 patients atteints d'une leucémie myéloïde aiguë du groupe CBF, cette étude française identifie des profils différents de gènes mutés selon la présence d'une translocation t(8;21) ou d'une inversion inv(16)

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez, Nicolas ; Marceau-Renaut, Alice ; Boissel, Nicolas ; Petit, Arnaud ; Bucci, Maxime ; Geffroy, Sandrine ; Lapillonne, Helene ; Renneville, Aline ; Ragu, Christine ; Figeac, Martin ; Celli-Lebras, Karine ; Lacombe, Catherine ; Micol, Jean-Baptiste ; Abdel-Wahab, Omar ; Cornillet, Pascale ; Ifrah, Norbert ; Dombret, Hervé ; Leverger, Guy ; Jourdan, Eric ; Preudhomme, Claude

Recurrent mutations in chromatin modifiers and cohesin were observed in t(8;21) AML but not inv(16) AML.t(8;21) AML patients with mutations in kinase signaling plus chromatin modifiers or cohesin members had the highest risk of relapse. Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been recognized as unique entities within AML and are usually reported together as core binding factor AML (CBF-AML). However, there is considerable clinical and biological heterogeneity within this group [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels la délétion de régions chromosomiques en lien avec la perte du gène TP53 favorise le développement d’un lymphome ou d’une leucémie

Deletions linked to TP53 loss drive cancer through p53-independent mechanisms

Liu, Yu ; Chen, Chong ; Xu, Zhengmin ; Scuoppo, Claudio ; Rillahan, Cory D. ; Gao, JianJiong ; Spitzer, Barbara ; Bosbach, Benedikt ; Kastenhuber, Edward R. ; Baslan, Timour ; Ackermann, Sarah ; Cheng, Lihua ; Wang, Qingguo ; Niu, Ting ; Schultz, Nikolaus ; Levine, Ross L. ; Mills, Alea A. ; Lowe, Scott W.

Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a ‘loss of heterozygosity’ deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels des macrophages CD169+ exercent une fonction de suppresseur de tumeurs dans les mélanomes

SCS macrophages suppress melanoma by restricting tumor-derived vesicle–B cell interactions

Pucci, Ferdinando ; Garris, Christopher ; Lai, Charles P. ; Newton, Andita ; Pfirschke, Christina ; Engblom, Camilla ; Alvarez, David ; Sprachman, Melissa ; Evavold, Charles ; Magnuson, Angela ; von Andrian, Ulrich H. ; Glatz, Katharina ; Breakefield, Xandra O. ; Mempel, Thorsten R. ; Weissleder, Ralph ; Pittet, Mikael J.

Tumor-derived extracellular vesicles (tEVs) are important signals in tumor-host cell communication. Yet, how endogenously produced tEVs impact the host in different areas of the body remains unclear. Here we combine imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169+ macrophages in tumor-draining lymph nodes (tdLNs) [...]

Menée à l'aide d'une technique de séquençage à haut débit de l'ARN et à l'aide d'une base de données de gènes codant pour des protéines de surface cellulaire, cette étude identifie une telle protéine, LINGO1, exprimée de façon spécifique sur la surface des cellules de sarcome d'Ewing

Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target

Town, Jennifer ; Pais, Helio ; Harrison, Sally ; Stead, Lucy F. ; Bataille, Carole ; Bunjobpol, Wilawan ; Zhang, Jing ; Rabbitts, Terence H.

The cell surface proteome of tumors mediates the interface between the transformed cells and the general microenvironment, including interactions with stromal cells in the tumor niche and immune cells such as T cells. In addition, the cell surface proteome of individual cancers defines biomarkers for that tumor type and potential proteins that can be the target of antibody-mediated therapy. We have used next-generation deep RNA sequencing (RNA-seq) coupled to an in-house database of genes [...]

Menée sur des lignées cellulaires de différents types de cancer (foie, prostate, sein), cette étude met en évidence des mécanismes par lesquels le facteur de transcription FOXA1 régule la progression du cancer de façon spécifique dans chaque lignée

FOXA1 defines cancer cell specificity

Zhang, Gaihua ; Zhao, Yongbing ; Liu, Yi ; Kao, Li-Pin ; Wang, Xiao ; Skerry, Benjamin ; Li, Zhaoyu

A transcription factor functions differentially and/or identically in multiple cell types. However, the mechanism for cell-specific regulation of a transcription factor remains to be elucidated. We address how a single transcription factor, forkhead box protein A1 (FOXA1), forms cell-specific genomic signatures and differentially regulates gene expression in four human cancer cell lines (HepG2, LNCaP, MCF7, and T47D). FOXA1 is a pioneer transcription factor in organogenesis and cancer [...]

Menée in vitro et in vivo sur des modèles de neuroblastome, cette étude met en évidence le rôle joué par l'hexokinase 2 dans le processus métastatique

Hexokinase 2 is a determinant of neuroblastoma metastasis

Edry Botzer, Liat ; Maman, Shelly ; Sagi-Assif, Orit ; Meshel, Tsipi ; Nevo, Ido ; Yron, Ilana ; Witz, Isaac P.

Background: Intersecting a genome-wide expression profile of metastatic and nonmetastatic human neuroblastoma xenograft variants with expression profiles of tumours from stage 1 and 4 neuroblastoma patients, we previously characterised hexokinase 2 (HK2) as a gene whose expression was upregulated in both metastatic neuroblastoma variants and tumours from stage 4 neuroblastoma patients. Methods: Local and metastatic neuroblastoma cell variants as well as metastatic neuroblastoma cells [...]

Menée à l'aide de modèles murins de cancer du pancréas, cette étude met en évidence des mécanismes par lesquels, dans le micro-environnement tumoral, la signalisation TGF-bêta favorise le développement d'une tumeur

TGFβ signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis

Principe, Daniel R ; DeCant, Brian ; Mascarinas, Emman ; Wayne, Elizabeth ; Diaz, Andrew ; Akagi, Naomi ; Hwang, Rosa F. ; Pasche, Boris ; Dawson, David W. ; Fang, Deyu ; Bentrem, David J. ; Munshi, Hidayatullah G. ; Jung, Barbara ; Grippo, Paul J

In early pancreatic carcinogenesis, TGFβ acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFβ appears to promote tumor progression. Therefore, to better understand the contributions of TGFβ signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFβ signals facilitated pancreatic tumorigenesis, whereas [...]

Menée à l'aide d'une technique d'imagerie sur des modèles murins, cette étude met en évidence la réponse du système immunitaire à l’arrivée de cellules tumorales circulantes dans le poumon

Visualization of immediate immune responses to pioneer metastatic cells in the lung

Headley, Mark B. ; Bins, Adriaan ; Nip, Alyssa ; Roberts, Edward W. ; Looney, Mark R. ; Gerard, Audrey ; Krummel, Matthew F.

Lung metastasis is the lethal determinant in many cancers and a number of lines of evidence point to monocytes and macrophages having key roles in its development. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue, and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice6 for [...]