Menée à l'aide de modèles murins de gliomes pédiatriques, cette étude met en évidence un mécanisme par lequel une mutation G328V au niveau du gène du récepteur ACVR1 induit l'arrêt de la différenciation des cellules gliales et favorise, en présence d'autres mutations (Hist1h3bK27M et Pik3caH1047R), la tumorigenèse

Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas

Fortin, Jerome ; Tian, Ruxiao ; Zarrabi, Ida ; Hill, Graham ; Williams, Eleanor ; Sanchez-Duffhues, Gonzalo ; Thorikay, Midory ; Ramachandran, Parameswaran ; Siddaway, Robert ; Wong, Jong Fu ; Wu, Annette ; Apuzzo, Lorraine N. ; Haight, Jillian ; You-Ten, Annick ; Snow, Bryan E. ; Wakeham, Andrew ; Goldhamer, David J. ; Schramek, Daniel ; Bullock, Alex N. ; Dijke, Peter ten ; Hawkins, Cynthia ; Mak, Tak W.

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate [...]

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la perte d'expression de la protéine p16 (INK4a) sans altération de l'expression de la protéine p19 (ARF) favorise le développement d'un carcinome épidermoïde invasif

Specific deletion of p16INK4a with retention of p19ARF enhances the development of invasive oral squamous cell carcinoma

Ishida, Kazuhisa ; Tomita, Hiroyuki ; Kanayama, Tomohiro ; Noguchi, Kei ; Niwa, Ayumi ; Kawaguchi, Masaya ; Miyai, Masafumi ; Matsuo, Mikiko ; Imaizumi, Yuko ; Kato, Keizo ; Hatano, Yuichiro ; Hirata, Akihiro ; Okada, Hideshi ; Shibata, Toshiyuki ; Hara, Akira

The cyclin dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16INK4a and p14ARF (p19Arf in mice), encoding two unrelated proteins in alternative reading frames. Previous reports suggest that p16INK4a and p14ARF alterations independently exhibit differential roles, and p16INK4a is more closely associated with a poor prognosis in oral cancer. However, the role of p16INK4a -specific loss in oral squamous cell [...]

Menée à l'aide d'échantillons de cancer de l'estomac de stade avancé et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la protéine DAXX inhibe les cellules souches cancéreuses et la transition épithélio-mésenchymateuse

DAXX inhibits cancer stemness and epithelial–mesenchymal transition in gastric cancer

Wu, Chaofan ; Ding, Hui ; Wang, Shuochen ; Li, Yangxin ; Liu, Song-Bai ; Wang, Xiaoxiao ; Zheng, Jiqing ; Xue, Ting ; Amin, Hesham M. ; Song, Yao-Hua ; Zhou, Jin

Background : DAXX is a transcription repressor that has been implicated in several types of cancers, but its role in the development of gastric cancer remains unknown. Methods : We analysed the expression of DAXX in 83 pairs of gastric cancer samples, including neoplastic and adjacent tissues, and correlated the expression levels with clinical stages. We also investigated the molecular mechanisms by which DAXX downregulation promotes cancer growth using both in vitro and in vivo models. Results [...]

Menée sur le métazoaire Hydra oligactis et à l'aide d'une souche bactérienne (Turneriella parva), cette étude met en évidence le rôle des interactions entre les bactéries pathogènes et le microbiote de l'hôte dans la tumorigenèse

Dynamic interactions within the host-associated microbiota cause tumor formation in the basal metazoan Hydra

Rathje, Kai ; Mortzfeld, Benedikt ; Hoeppner, Marc P. ; Taubenheim, Jan ; Bosch, Thomas C. G. ; Klimovich, Alexander

Author summary Here we follow up on our initial observation of tumor formation in the basal metazoan Hydra and demonstrate that tumor development in one of the evolutionary oldest animals is caused by a dynamic interplay between an environmental spirochete, the host-associated resident microbiota, and the tissue homeostasis within the animal. Unexpectedly, the pathogenicity of the environmental bacterium Turneriella is context-dependent: the virulence of this pathogen requires the presence of a [...]

Menée à l'aide d'une lignée isogénique de cellules épithéliales du sein, cette étude compare les effets de 6 oncogènes (KRAS G12V, surexpression de HER2, EGFR L858R, BRAFV600E, MEK S218D/S222D phosphomimétiques et AKT myristoylé) sur l'expression de 700 protéines de surface

Broad and thematic remodeling of the surfaceome and glycoproteome on isogenic cells transformed with driving proliferative oncogenes

Leung, Kevin K. ; Wilson, Gary M. ; Kirkemo, Lisa L. ; Riley, Nicholas M. ; Coon, Joshua J. ; Wells, James A.

The cell surface proteome (surfaceome) mediates interactions between the cell and the extracellular environment and is a major target for immunotherapy in cancer. Here, we compared how six neighboring proliferative oncogenes cause large and bidirectional change in expression of some 700 surface proteins. These large changes converge to common functional consequences that are reversed by small-molecule inhibition of the MAPK pathway. We further complemented the surfaceome analysis with bottom-up [...]

Menée in vitro et à l'aide de modèles murins, cette étude démontre que l'altération du clivage de l'ectodomaine de l'anhydrase carbonique IX des cellules cancéreuses renforce le phénotype tumorigène et métastatique de ces dernières

Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells

Kajanova, Ivana ; Zatovicova, Miriam ; Jelenska, Lenka ; Sedlakova, Olga ; Barathova, Monika ; Csaderova, Lucia ; Debreova, Michaela ; Lukacikova, Lubomira ; Grossmannova, Katarina ; Labudova, Martina ; Golias, Tereza ; Svastova, Eliska ; Ludwig, Andreas ; Muller, Petr ; Vojtesek, Borivoj ; Pastorek, Jaromir ; Pastorekova, Silvia

Background : Carbonic anhydrase IX (CA IX) is a hypoxia-induced enzyme regulating tumour pH and facilitating cell migration/invasion. It is primarily expressed as a transmembrane cell-surface protein, but its ectodomain can be shed by ADAM17 to extracellular space. This study aims to elucidate the impact of CA IX shedding on cancer cells. Methods : We generated a non-shed CA IX mutant by deletion of amino acids 393–402 from the stalk region and studied its phenotypic effects compared to [...]

Menée à l'aide de lignées cellulaires de mélanome humain, de modèles murins et de tissus tumoraux issus de patients atteints d'un carcinome du poumon non à petites cellules, cette étude met en évidence un mécanisme par lequel l'inhibition du récepteur ADORA1 favorise l'échappement immunitaire de la tumeur en régulant la voie impliquant le facteur de transcription ATF3 et la protéine PD-L1

ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis

Liu, Hong ; Kuang, Xinwei ; Zhang, Yongchang ; Ye, Youqiong ; Li, Jialu ; Liang, Long ; Xie, Zuozhong ; Weng, Liang ; Guo, Jia ; Li, Hui ; Ma, Fangyu ; Chen, Xiaodan ; Zhao, Shuang ; Su, Juan ; Yang, Nong ; Fang, Fang ; Xie, Yang ; Tao, Juan ; Zhang, Jianglin ; Chen, Mingliang ; Peng, Cong ; Sun, Lunquan ; Zhang, Xin ; Liu, Jing ; Han, Leng ; Xu, Xiaowei ; Hung, Mien-Chie ; Chen, Xiang

Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma [...]

Menée sur des lignées cellulaires de lymphome ou de leucémie de patients adultes et menée à l'aide de modèles murins, cette étude met en évidence la surexpression de l'ectonucléotidase CD39 sur les cellules cancéreuses ainsi que la fonction immunosuppressive de cette ectonucléotidase

Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function

Nagate, Yasuhiro ; Ezoe, Sachiko ; Fujita, Jiro ; Okuzakis, Daisuke ; Motooka, Daisuke ; Ishibashi, Tomohiko ; Ichii, Michiko ; Tanimura, Akira ; Kurashige, Masako ; Morii, Eiichi ; Fukushima, Takuya ; Suehiro, Youko ; Yokota, Takafumi ; Shibayama, Hirohiko ; Oritani, Kenji ; Kanakura, Yuzuru

Adult T-cell leukemia/lymphoma (ATLL) patients have an extremely poor prognosis, partly due to their immunosuppressive state. The majority of ATLL patients have leukemic cells with phenotype similar to Tregs, prompting suggestions that ATLL cells themselves have immunosuppressive functions. In this study, we detected CD39 expression on ATLL cells, particularly frequent on aggressive subtypes. CD39 and CD73 convert extracellular adenosine triphosphate (ATP) into adenosine, a key player in Tregs’ [...]

Menée in vitro, cette étude met en évidence le rôle de glycosyltransférases dans le caractère agressif des cancers du pancréas

Global analysis of human glycosyltransferases reveals novel targets for pancreatic cancer pathogenesis

Gupta, Rohitesh ; Leon, Frank ; Thompson, Christopher M. ; Nimmakayala, Ramakrishna ; Karmakar, Saswati ; Nallasamy, Palanisamy ; Chugh, Seema ; Prajapati, Dipakkumar R. ; Rachagani, Satyanarayana ; Kumar, Sushil ; Ponnusamy, Moorthy P.

Background : Several reports have shown the role of glycosylation in pancreatic cancer (PC), but a global systematic screening of specific glycosyltransferases (glycoTs) in its progression remains unknown. Methods : We demonstrate a rigorous top-down approach using TCGA-based RNA-Seq analysis, multi-step validation using RT-qPCR, immunoblots and immunohistochemistry. We identified six unique glycoTs (B3GNT3, B4GALNT3, FUT3, FUT6, GCNT3 and MGAT3) in PC pathogenesis and studied their function [...]

Menée in vitro et à l'aide d'un modèle murin de cancer du poumon, cette étude met en évidence un mécanisme par lequel le cuivre, en régulant l'activité de ULK1 et de ULK2 (deux enzymes impliquées dans l'autophagie cellulaire), favorise le développement tumoral

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Tsang, Tiffany ; Posimo, Jessica M. ; Gudiel, Andrea A. ; Cicchini, Michelle ; Feldser, David M. ; Brady, Donita C.

Although the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a non-traditional role for Cu as a modulator of kinase signalling is emerging. Here, we found that Cu is required for the activity of the autophagic kinases ULK1 and ULK2(ULK1/2) through a direct Cu–ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt the binding of Cu reduced ULK1/2-dependent signalling and [...]

Menée à partir de données du projet "The Cancer Genome Atlas" portant sur 501 carcinomes épidermoïdes primitifs du poumon et menée in vitro, cette étude met en évidence un mécanisme par lequel les fibroblastes associés au cancer favorisent l'immunosuppression en induisant les cellules myéloïdes suppressives monocytaires génératrices d'espèces réactives de l'oxygène

Cancer-Associated Fibroblasts Promote Immunosuppression by Inducing ROS-Generating Monocytic MDSCs in Lung Squamous Cell Carcinoma

Xiang, Handan ; Ramil, Carlo P. ; Hai, Josephine ; Zhang, Chunsheng ; Wang, Huijun ; Watkins, Amanda A. ; Afshar, Roshi ; Georgiev, Peter ; Sze, Marc A. ; Song, Xuelei S. ; Curran, Patrick J. ; Cheng, Mangeng ; Miller, J. Richard ; Sun, Dongyu ; Loboda, Andrey ; Jia, Yanlin ; Moy, Lily Y. ; Chi, An ; Brandish, Philip E.

Cancer-associated fibroblasts (CAF) represent a functionally heterogeneous population of activated fibroblasts that constitutes a major component of tumor stroma. Although CAFs have been shown to promote tumor growth and mediate resistance to chemotherapy, the mechanisms by which they may contribute to immune suppression within the tumor microenvironment (TME) in lung squamous cell carcinoma (LSCC) remain largely unexplored. Here, we identified a positive correlation between CAF and monocytic [...]

Menée sur des lignées cellulaires de cancer colorectal et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel le microARN miR-802, en régulant la petite GTPase Ran, réduit la prolifération des cellules cancéreuses et le processus métastatique

Regulation of the small GTPase Ran by miR-802 modulates proliferation and metastasis in colorectal cancer cells

Wang, Xin ; Li, Danxiu ; Sun, Lina ; Shen, Gaofei ; Liu, Hao ; Guo, Hao ; Ge, Minghui ; Liang, Junrong ; Chen, Ping ; Zhou, Jinchi ; Cao, Tianyu ; Wang, Qi ; Gao, Xiaoliang ; Tong, Mingfu ; Hu, Sijun ; Nie, Yongzhan ; Fan, Daiming ; Zhao, Xiaodi ; Lu, Yuanyuan

Background : The small GTPase Ran is upregulated in multiple cancers and fundamental for cancer cell survival and progression, but its significance and molecular mechanisms in colorectal cancer (CRC) remain elusive. Methods : Ran expression was detected in CRC cell lines and tumour tissues. In vitro and in vivo functional assays were performed to examine the effects of Ran on cell proliferation and metastasis. The pathways and effectors regulated by Ran were explored by an unbiased screening. [...]

Menée à l'aide de lignées cellulaires de cancer rénal humain à cellules claires et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel des modifications épigénétiques favorisent l'expression de gènes impliqués dans l'inflammation de la tumeur ainsi que le processus métastatique dépendant des neutrophiles

Epigenetic remodelling shapes inflammatory renal cancer and neutrophil-dependent metastasis

Nishida, Jun ; Momoi, Yusaku ; Miyakuni, Kosuke ; Tamura, Yusuke ; Takahashi, Kei ; Koinuma, Daizo ; Miyazono, Kohei ; Ehata, Shogo

Advanced clear cell renal cell carcinoma (ccRCC) frequently causes systemic inflammation. Recent studies have shown that cancer cells reshape the immune landscape by secreting cytokines or chemokines. This phenotype, called cancer-cell-intrinsic inflammation, triggers a metastatic cascade. Here, we identified the functional role and regulatory mechanism of inflammation driven by advanced ccRCC cells. The inflammatory nature of advanced ccRCC was recapitulated in a preclinical model of ccRCC. [...]

Menée à l'aide d'une lignée cellulaire de cancer mammaire et d'un modèle murin, cette étude met en évidence un mécanisme par lequel la peptidyl-arginine désiminase 4 des cellules cancéreuses favorise la formation d'un réseau de chromatine extracellulaire et le développement de métastases pulmonaires

Endogenous PAD4 in Breast Cancer Cells Mediates Cancer Extracellular Chromatin Network Formation and Promotes Lung Metastasis

Shi, Lai ; Yao, Huanling ; Liu, Zheng ; Xu, Ming ; Tsung, Allan ; Wang, Yanming

Peptidyl arginine deiminase 4 (PAD4/PADI4) is a posttranslational modification enzyme that converts protein arginine or mono-methylarginine to citrulline. The PAD4-mediated hypercitrullination reaction in neutrophils causes the release of nuclear chromatin to form a chromatin network termed neutrophil extracellular traps (NET). NETs were first described as antimicrobial fibers that bind and kill bacteria. However, it is not known whether PAD4 can mediate the release of chromatin DNA into the [...]

Menée sur des lignées cellulaires de gliome, cette étude met en évidence le rôle de l'homéostasie redox dépendante de la sérine dans la régulation de la survie des cellules de glioblastome

Serine-dependent redox homeostasis regulates glioblastoma cell survival

Engel, Anna L. ; Lorenz, Nadja I. ; Klann, Kevin ; Münch, Christian ; Depner, Cornelia ; Steinbach, Joachim P. ; Ronellenfitsch, Michael W. ; Luger, Anna-Luisa

Background : The amino acid serine is an important substrate for biosynthesis and redox homeostasis. We investigated whether glioblastoma (GBM) cells are dependent on serine for survival under conditions of the tumour microenvironment. Methods : Serine availability in GBM cells was modulated pharmacologically, genetically and by adjusting serine and glycine concentrations in the culture medium. Cells were investigated for regulation of serine metabolism, proliferation, sensitivity to [...]

Menée à partir d'échantillons sériques et d'échantillons tumoraux prélevés sur 34 patients atteints d'un glioblastome ou d'un méningiome, cette étude analyse la corrélation entre l'altération du niveau sérique de ferritine avant chirurgie et la synthèse intratumorale de ferritine, puis examine le rôle de cette synthèse dans le développement de la tumeur

Ferritin in glioblastoma

Jaksch-Bogensperger, Heidi ; Spiegl-Kreinecker, Sabine ; Arosio, Paolo ; Eckl, Peter ; Golaszewski, Stefan ; Ebner, Yvonne ; Al-Schameri, Rahman ; Strasser, Peter ; Weis, Serge ; Bresgen, Nikolaus

Elevated levels of serum ferritin (SF) are observed in several types of cancer; however, little is known on the association between ferritin and glioma, the most frequent type of human primary brain tumour. Here we report that GBM patients show significantly increased pre-surgical SF levels (i.e. ferritinaemia) within the SF reference range and a marked ferritin immunoreactivity of resected tumour tissue. Our findings account for an indirect association between ferritin synthesis in [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel le co-activateur transcriptionnel YAP1 favorise la survenue et la progression d'un carcinome épidermoïde de la cavité buccale

YAP1 is a potent driver of the onset and progression of oral squamous cell carcinoma

Omori, Hirofumi ; Nishio, Miki ; Masuda, Muneyuki ; Miyachi, Yosuke ; Ueda, Fumihito ; Nakano, Takafumi ; Sato, Kuniaki ; Mimori, Koshi ; Taguchi, Kenichi ; Hikasa, Hiroki ; Nishina, Hiroshi ; Tashiro, Hironori ; Kiyono, Tohru ; Mak, Tak Wah ; Nakao, Kazuwa ; Nakagawa, Takashi ; Maehama, Tomohiko ; Suzuki, Akira

Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common group of cancers in the world, and patients have a poor prognosis. Here, we present data indicating that YAP1 may be a strong driver of the onset and progression of oral SCC (OSCC), a major subtype of HNSCC. Mice with tongue-specific deletion of Mob1a/b and thus endogenous YAP1 hyperactivation underwent surprisingly rapid and highly reproducible tumorigenesis, developing tongue carcinoma in situ within 2 weeks and invasive [...]

Cet article présente le développement, à partir de cellules souches pluripotentes induites, d'un nouveau modèle de cellules souches de cancer hépatique

A novel model of liver cancer stem cells developed from induced pluripotent stem cells

Afify, Said M. ; Sanchez Calle, Anna ; Hassan, Ghmkin ; Kumon, Kazuki ; Nawara, Hend M. ; Zahra, Maram H. ; Mansour, Hager M. ; Khayrani, Apriliana Cahya ; Alam, Md Jahangir ; Du, Juan ; Seno, Akimasa ; Iwasaki, Yoshiaki ; Seno, Masaharu

Background : Liver cancer is the second most common cause of cancer-related death. Every type of tumours including liver cancer contains cancer stem cells (CSCs). To date, the molecular mechanism regulating the development of liver CSCs remains unknown. Methods : In this study, we tried to generate a new model of liver CSCs by converting mouse induced pluripotent stem cells (miPSCs) with hepatocellular carcinoma (HCC) cell line Huh7 cells conditioned medium (CM). miPSCs treated with CM were [...]

Menée sur des lymphocytes T de leucémie lymphoblastique aiguë, cette étude analyse l'architecture tridimensionnelle de la chromatine et examine l'effet d'agents pharmacologiques sur cette architecture

Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

Kloetgen, Andreas ; Thandapani, Palaniraja ; Ntziachristos, Panagiotis ; Ghebrechristos, Yohana ; Nomikou, Sofia ; Lazaris, Charalampos ; Chen, Xufeng ; Hu, Hai ; Bakogianni, Sofia ; Wang, Jingjing ; Fu, Yi ; Boccalatte, Francesco ; Zhong, Hua ; Paietta, Elisabeth ; Trimarchi, Thomas ; Zhu, Yixing ; Van Vlierberghe, Pieter ; Inghirami, Giorgio G. ; Lionnet, Timothee ; Aifantis, Iannis ; Tsirigos, Aristotelis

Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer–promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in [...]