Cet article passe en revue les travaux récents sur les mécanismes par lesquels des mutations de gènes modifiant la chromatine favorisent le développement d'un lymphome folliculaire

Chromatin modifying gene mutations in follicular lymphoma

Green, Michael R.

Follicular lymphoma (FL) is an indolent malignancy of germinal center B (GCB)-cells. Although the overall survival of FL patients has recently improved with the introduction of novel therapies, there is significant heterogeneity in patient outcome and a need for rationally designed therapeutic strategies that target disease biology. Next generation sequencing studies have identified chromatin modifying gene (CMG) mutations as a hallmark of FL, highlighting epigenetic modifiers as an attractive [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels une mutation inactivant le gène BRCA1 induit la formation de duplication en tandem de séquences d'environ 10 kilobases

Mechanism of tandem duplication formation in BRCA1-mutant cells

Willis, Nicholas A. ; Frock, Richard L. ; Menghi, Francesca ; Duffey, Erin E. ; Panday, Arvind ; Camacho, Virginia ; Hasty, E. Paul ; Liu, Edison T. ; Alt, Frederick W. ; Scully, Ralph

Small, approximately 10-kilobase microhomology-mediated tandem duplications are abundant in the genomes of BRCA1-linked but not BRCA2-linked breast cancer. Here we define the mechanism underlying this rearrangement signature. We show that, in primary mammalian cells, BRCA1, but not BRCA2, suppresses the formation of tandem duplications at a site-specific chromosomal replication fork barrier imposed by the binding of Tus proteins to an array of Ter sites. BRCA1 has no equivalent role at [...]

Menée in vitro et in vivo sur des modèles de tumeur stromale gastro-intestinale, cette étude met en évidence des mécanismes par lesquels la protéine FOXF1 favorise la prolifération des cellules cancéreuses

FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST)

Ran, Leili ; Chen, Yuedan ; Sher, Jessica ; Wong, Wai Pung E. ; Murphy, Devan ; Zhang, Jenny Q. ; Li, Dan ; Deniz, Kemal ; Sirota, Inna ; Cao, Zhen ; Wang, Shangqian ; Guan, Youxin ; Shukla, Shipra ; Li, Katie Yang ; Chramiec, Alan ; Xie, Yuanyuan ; Zheng, Deyou ; Koche, Richard P. ; Antonescu, Cristina R. ; Chen, Yu ; Chi, Ping

The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behaviour and shapes treatment responses in distinct cancer types. Here, we uncover that in GIST, the forkhead family member, FOXF1, directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal (ICC) lineage-specification and GIST tumorigenesis. Further, FOXF1 co-localizes with ETV1 at enhancers and functions [...]

Menée à l'aide de modèles murins de carcinome hépatocellulaire fibrolamellaire (une forme rare de cancer du foie affectant principalement les adolescents et les jeunes adultes), cette étude met en évidence des mécanismes par lesquels une fusion des gènes DNAJB1 et PRKACA favorise le développement de la maladie

DNAJB1–PRKACA fusion kinase interacts with beta-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma

Kastenhuber, Edward R. ; Lalazar, Gadi ; Houlihan, Shauna L. ; Tschaharganeh, Darjus F. ; Baslan, Timour ; Chen, Chi-Chao ; Requena, David ; Tian, Sha ; Bosbach, Benedikt ; Wilkinson, John E. ; Simon, Sanford M. ; Lowe, Scott W.

A segmental deletion resulting in DNAJB1–PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here we implement CRISPR-Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of either the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels des ARNs non codants interagissent en réseaux au cours du développement d'une tumeur

Non-coding RNA networks in cancer

Anastasiadou, Eleni ; Jacob, Leni S. ; Slack, Frank J.

Thousands of unique non-coding RNA (ncRNA) sequences exist within cells. Work from the past decade has altered our perception of ncRNAs from 'junk' transcriptional products to functional regulatory molecules that mediate cellular processes including chromatin remodelling, transcription, post-transcriptional modifications and signal transduction. The networks in which ncRNAs engage can influence numerous molecular targets to drive specific cell biological responses and fates. Consequently, [...]

Menée in vitro et in vivo sur des modèles de cancer du côlon-rectum, du sein ou du pancréas, cette étude met en évidence des mécanismes par lesquels, via le renouvellement continu de néoantigènes, l'inactivation de gènes impliqués dans la réparation des mésappariements de l'ADN déclenche une réponse immunitaire antitumorale

Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth

Germano, Giovanni ; Lamba, Simona ; Rospo, Giuseppe ; Barault, Ludovic ; Magrì, Alessandro ; Maione, Federica ; Russo, Mariangela ; Crisafulli, Giovanni ; Bartolini, Alice ; Lerda, Giulia ; Siravegna, Giulia ; Mussolin, Benedetta ; Frapolli, Roberta ; Montone, Monica ; Morano, Federica ; de Braud, Filippo ; Amirouchene-Angelozzi, Nabil ; Marsoni, Silvia ; D’Incalci, Maurizio ; Orlandi, Armando ; Giraudo, Enrico ; Sartore-Bianchi, Andrea ; Siena, Salvatore ; Pietrantonio, Filippo ; Di Nicolantonio, Federica ; Bardelli, Alberto

Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression. Cancers deficient in MMR frequently show favourable prognosis and indolent progression. The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their [...]

Menée in vitro et in vivo sur des modèles de cancer du sein et de cancer du poumon, cette étude met en évidence des mécanismes par lesquels, en induisant la production d'interleukine 22 par des lymphocytes T CD4+ à mémoire, les cellules cancéreuses favorisent la croissance tumorale

Cancer cells induce interleukin-22 production from memory CD4+ T cells via interleukin-1 to promote tumor growth

Voigt, Cornelia ; May, Peter ; Gottschlich, Adrian ; Markota, Anamarija ; Wenk, Daniel ; Gerlach, Inga ; Voigt, Sebastian ; Stathopoulos, Georgios T. ; Arendt, Kristina A. M. ; Heise, Constanze ; Rataj, Felicitas ; Janssen, Klaus-Peter ; Königshoff, Melanie ; Winter, Hauke ; Himsl, Isabelle ; Thasler, Wolfgang E. ; Schnurr, Max ; Rothenfußer, Simon ; Endres, Stefan ; Kobold, Sebastian

IL-22 has been identified as a cancer-promoting cytokine that is secreted by infiltrating immune cells in several cancer models. We hypothesized that IL-22 regulation would occur at the interface between cancer cells and immune cells. Breast and lung cancer cells of murine and human origin induced IL-22 production from memory CD4+ T cells. In the present study, we found that IL-22 production in humans is dependent on activation of the NLRP3 inflammasome with the subsequent release of IL-1β from [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels un ensemble de gènes dont l'expression est régulée par l'enzyme METTL3 favorisent le développement d'une leucémie myéloïde aiguë

Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control

Barbieri, Isaia ; Tzelepis, Konstantinos ; Pandolfini, Luca ; Shi, Junwei ; Millán-Zambrano, Gonzalo ; Robson, Samuel C. ; Aspris, Demetrios ; Migliori, Valentina ; Bannister, Andrew J. ; Han, Namshik ; De Braekeleer, Etienne ; Ponstingl, Hannes ; Hendrick, Alan ; Vakoc, Christopher R. ; Vassiliou, George S. ; Kouzarides, Tony

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3–METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of [...]

Menée in vitro et in vivo sur des modèles d'adénocarcinome du pancréas, cette étude met en évidence des mécanismes par lesquels l'expression de deux cadhérines à la surface des cellules cancéreuses favorise, de façon complémentaire, les processus invasif et métastatique

Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

Siret, Carole ; Dobric, Aurélie ; Martirosyan, Anna ; Terciolo, Chloé ; Germain, Sébastien ; Bonier, Renaté ; Dirami, Thassadite ; Dusetti, Nelson ; Tomasini, Richard ; Rubis, Marion ; Garcia, Stéphane ; Iovanna, Juan ; Lombardo, Dominique ; Rigot, Véronique ; André, Frédéric

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an extensive tissue invasion and an early formation of metastasis. Alterations in the expression of cadherins have been reported in PDAC. Yet, how these changes contribute to tumour progression is poorly understood. Here, we investigated the relationship between cadherins expression and PDAC development. Methods: Cadherins expression was assessed by immunostaining in both human and murine tissue specimens. We have generated [...]

Menée à l'aide d'un modèle murin d'adénocarcinome du poumon induit par un gène KRas muté, cette étude met en évidence des mécanismes par lesquels, via les signalisations CCL9 et IL-23, la protéine Myc favorise la suppression de la réponse immunitaire antitumorale dans le micro-environnement

Myc Cooperates with Ras by Programming Inflammation and Immune Suppression

Kortlever, Roderik M. ; Sodir, Nicole M. ; Wilson, Catherine H. ; Burkhart, Deborah L. ; Pellegrinet, Luca ; Brown Swigart, Lamorna ; Littlewood, Trevor D. ; Evan, Gerard I.

The two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRasG12D-driven adenomas, we find that co-activation of Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. We identify epithelial-derived signaling molecules CCL9 and IL-23 as the principal instructing signals for stromal reprogramming. CCL9 [...]

Menée in vitro et in vivo sur des modèles d'adénocarcinome du poumon, cette étude met en évidence des mécanismes par lesquels, en protégeant les cellules cancéreuses d'une ferroptose (mort cellulaire non apoptotique) en réponse à un stress oxydant, l'enzyme NFS1 favorise la croissance tumorale

NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis

Alvarez, Samantha W. ; Sviderskiy, Vladislav O. ; Terzi, Erdem M. ; Papagiannakopoulos, Thales ; Moreira, Andre L. ; Adams, Sylvia ; Sabatini, David M. ; Birsoy, Kivanc ; Possemato, Richard

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using loss-of-function screening based on RNA interference, we show that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3–8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron–sulfur cluster biosynthetic enzyme NFS1. Mammary or [...]

Menée sur des lignées cellulaires et des modèles murins de cancer de la prostate n'exprimant pas le gène PTEN, cette étude met en évidence des mécanismes par lesquels une activation anormale du gène RUNX2 favorise le remodelage du micro-environnement tumoral

PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

Yang, Yinhui ; Bai, Yang ; He, Yundong ; Zhao, Yu ; Chen, Jiaxiang ; Ma, Linlin ; Pan, Yunqian ; Hinten, Michael ; Zhang, Jun ; Karnes, R. Jeffrey ; Kohli, Manish ; Westendorf, Jennifer J. ; Li, Benyi ; Zhu, Runzhi ; Huang, Haojie ; Xu, Wanhai

Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood.  Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell [...]

Menée à l'aide de xénogreffes d'adénocarcinome colorectal sur des modèles murins, cette étude met notamment en évidence la présence de l'espèce bactérienne Fusobacterium nucleatum dans les métastases à distance

Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer

Bullman, Susan ; Pedamallu, Chandra S. ; Sicinska, Ewa ; Clancy, Thomas E. ; Zhang, Xiaoyang ; Cai, Diana ; Neuberg, Donna ; Huang, Katherine ; Guevara, Fatima ; Nelson, Timothy ; Chipashvili, Otari ; Hagan, Timothy ; Walker, Mark ; Ramachandran, Aruna ; Diosdado, Begoña ; Serna, Garazi ; Mulet, Nuria ; Landolfi, Stefania ; Ramon y Cajal, Santiago ; Fasani, Roberta ; Aguirre, Andrew J. ; Ng, Kimmie ; Elez, Elena ; Ogino, Shuji ; Tabernero, Josep ; Fuchs, Charles S. ; Hahn, William C. ; Nuciforo, Paolo ; Meyerson, Matthew

Colorectal cancers comprise a complex mixture of malignant cells, non-transformed cells and microorganisms. Fusobacterium nucleatum is among the most prevalent bacterial species in colorectal cancer tissues. Here we show that colonization of human colorectal cancers with Fusobacterium and its associated microbiome, including Bacteroides, Selenomonas and Prevotella species, is maintained in distal metastases, demonstrating microbiome stability between paired primary-metastatic tumors. In situ [...]

Menée in vitro et in vivo sur des modèles de carcinome épidermoïde de la tête et du cou, cette étude met en évidence des mécanismes par lesquels, via la régulation de la signalisation de l'acide hyaluronique, la surexpression d'une isoforme de la protéine p63 favorise la prolifération des cellules cancéreuses et la résistance à une chimiothérapie

DeltaNp63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis

Compagnone, Mirco ; Gatti, Veronica ; Presutti, Dario ; Ruberti, Giovina ; Fierro, Claudia ; Markert, Elke Katrin ; Vousden, Karen H. ; Zhou, Huiqing ; Mauriello, Alessandro ; Anemone, Lucia ; Bongiorno-Borbone, Lucilla ; Melino, Gerry ; Peschiaroli, Angelo

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and several molecular pathways that underlie the molecular tumorigenesis of HNSCC have been identified. Among them, amplification or overexpression of ΔNp63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a ΔNp63-dependent transcriptional program able to regulate the metabolism and the signaling of hyaluronic acid (HA), the major component of the extracellular matrix (ECM). We found that [...]

A partir de données issues du projet "The Cancer Genome Atlas" et portant sur des carcinomes épidermoïdes de la tête et du cou, puis menée in vitro, cette étude met en évidence des mécanismes par lesquels la voie de signalisation NOTCH4-HEY1 favorise une transition épithélio-mésenchymateuse

The NOTCH4-HEY1 pathway induces epithelial mesenchymal transition in head and neck squamous cell carcinoma

Fukusumi, Takahito ; Guo, Theresa ; Sakai, Akihiro ; Ando, Mizuo ; Ren, Shuling ; Haft, Sunny ; Liu, Chao ; Amornphimoltham, Panomwat ; Gutkind, J. Silvio ; Califano, Joseph

Background: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood. Methods: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of [...]

A partir d'échantillons de sang périphérique, de tissu tumoral et de tissu sain prélevés sur 16 patientes atteintes d'un cancer du sein de stade précoce, cette étude analyse la structure clonale des lymphocytes T présents dans la tumeur, le tissu adjacent et le sang

T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire

Beausang, John F. ; Wheeler, Amanda J. ; Chan, Natalie H. ; Hanft, Violet R. ; Dirbas, Frederick M. ; Jeffrey, Stefanie S. ; Quake, Stephen R.

Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from [...]

A partir de l'analyse du transcriptome de 6 000 cellules issues d'échantillons tumoraux prélevés sur 18 patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude permet notamment d'affiner la classification en sous-groupes de la maladie

Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer

Puram, Sidharth V. ; Tirosh, Itay ; Parikh, Anuraag S. ; Patel, Anoop P. ; Yizhak, Keren ; Gillespie, Shawn ; Rodman, Christopher ; Luo, Christina L. ; Mroz, Edmund A. ; Emerick, Kevin S. ; Deschler, Daniel G. ; Varvares, Mark A. ; Mylvaganam, Ravi ; Rozenblatt-Rosen, Orit ; Rocco, James W. ; Faquin, William C. ; Lin, Derrick T. ; Regev, Aviv ; Bernstein, Bradley E.

-The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of -6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, [...]