Menée in vitro et à l'aide de modèles murins, cette étude analyse les mécanismes par lesquels la méthylation de la N6-adénosine de l'ARN régule la longueur des télomères et la stabilité génomique dans les cellules cancéreuses

Regulation of telomere homeostasis and genomic stability in cancer by N6-adenosine methylation (m6A)

Lee, Ji Hoon ; Hong, Juyeong ; Zhang, Zhao ; de la Peña Avalos, Bárbara ; Proietti, Cecilia J. ; Deamicis, Agustina Roldán ; Guzmán G, Pablo ; Lam, Hung-Ming ; Garcia, Jose ; Roudier, Martine P. ; Sisk, Anthony E. ; De La Rosa, Richard ; Vu, Kevin ; Yang, Mei ; Liao, Yiji ; Scheirer, Jessica ; Pechacek, Douglas ; Yadav, Pooja ; Rao, Manjeet K. ; Zheng, Siyuan ; Johnson-Pais, Teresa L. ; Leach, Robin J. ; Elizalde, Patricia V. ; Dray, Eloise ; Xu, Kexin

The role of RNA methylation on N6-adenosine (m6A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (HMBOX1) as an authentic target mRNA of m6A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m6A-mediated down-regulation of HMBOX1 causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine SLC38A4, en régulant l'axe Wnt/bêta

SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/beta-catenin/MYC/HMGCS2 axis

Li, Jie ; Li, Ming-han ; Wang, Tian-tian ; Liu, Xiao-ning ; Zhu, Xiao-ting ; Dai, Yun-zhang ; Zhai, Ke-chao ; Liu, Yong-da ; Lin, Jia-li ; Ge, Rui-liang ; Sun, Shu-han ; Wang, Fang ; Yuan, Ji-hang

Background : Many molecular alterations are shared by embryonic liver development and hepatocellular carcinoma (HCC). Identifying the common molecular events would provide a novel prognostic biomarker and therapeutic target for HCC. Methods : Expression levels and clinical relevancies of SLC38A4 and HMGCS2 were investigated by qRT-PCR, western blot, TCGA and GEO datasets. The biological roles of SLC38A4 were investigated by functional assays. The downstream signalling pathway of SLC38A4 was [...]

Menée in vitro et à l'aide d'un modèle murin de tumeur pulmonaire, cette étude met en évidence un mécanisme par lequel la protéine SAR1B, en fonction de la concentration intracellulaire de leucine, inhibe ou active la voie de signalisation du complexe protéique mTORC1

SAR1B senses leucine levels to regulate mTORC1 signalling

Chen, Jie ; Ou, Yuhui ; Luo, Rong ; Wang, Jie ; Wang, Dong ; Guan, Jialiang ; Li, Yi ; Xia, Peixue ; Chen, Peng R. ; Liu, Ying

The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels1. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B–GATOR2–mTORC1 [...]

Menée à l'aide de lignées cellulaires, cette étude met en évidence un mécanisme par lequel la voie de signalisation de la tyrosine kinase AXL et de son ligand GAS6 déclenche, via le remodelage de l'actine, le froissement des membranes des cellules cancéreuses, la macropinocytose et le processus invasif

The GAS6-AXL signaling pathway triggers actin remodeling that drives membrane ruffling, macropinocytosis, and cancer-cell invasion

Zdżalik-Bielecka, Daria ; Poświata, Agata ; Kozik, Kamila ; Jastrzębski, Kamil ; Schink, Kay Oliver ; Brewińska-Olchowik, Marta ; Piwocka, Katarzyna ; Stenmark, Harald ; Miączyńska, Marta

Metastasis remains the major cause of cancer-related deaths. Overactivation of receptor tyrosine kinase AXL has been correlated with cancer invasion and metastasis, resistance to therapies, and poor patient prognosis. However, the cellular processes activated by AXL and its ligand, GAS6, are largely unknown. Here, we identified a proximity interactome of AXL and revealed actin-dependent processes activated by GAS6-AXL, including membrane ruffling and macropinocytosis, that provide insights into [...]

Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude démontre que l'ADP-ribosylation des protéines ribosomales inhibe la traduction de l'ARN messager et permet de maintenir l'équilibre protéique dans les cellules cancéreuses

Ribosome ADP-ribosylation inhibits translation and maintains proteostasis in cancers

Challa, Sridevi ; Khulpateea, Beman R. ; Nandu, Tulip ; Camacho, Cristel V. ; Ryu, Keun W. ; Chen, Hao ; Peng, Yan ; Lea, Jayanthi S. ; Kraus, W. Lee

Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD+ synthesis plays an essential role in ovarian cancer by regulating translation and maintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD+ synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal [...]

Cette étude présente une approche utilisant l'intelligence artificielle pour identifier les mutations impliquées dans la tumorigenèse

In silico saturation mutagenesis of cancer genes

Muiños, Ferran ; Martínez-Jiménez, Francisco ; Pich, Oriol ; Gonzalez-Perez, Abel ; Lopez-Bigas, Nuria

Despite the existence of good catalogues of cancer genes1,2, identifying the specific mutations of those genes that drive tumorigenesis across tumour types is still a largely unsolved problem. As a result, most mutations identified in cancer genes across tumours are of unknown significance to tumorigenesis3. We propose that the mutations observed in thousands of tumours—natural experiments testing their oncogenic potential replicated across individuals and tissues—can be exploited to solve this [...]

Menée à l'aide d'un modèle murin et d'une analyse transcriptomique à l'échelle de la cellule, cette étude met en évidence le rôle des facteurs NF-

NF-κB–dependent IRF1 activation programs cDC1 dendritic cells to drive antitumor immunity

Ghislat, Ghita ; Cheema, Ammar S. ; Baudoin, Elodie ; Verthuy, Christophe ; Ballester, Pedro J. ; Crozat, Karine ; Attaf, Noudjoud ; Dong, Chuang ; Milpied, Pierre ; Malissen, Bernard ; Auphan-Anezin, Nathalie ; Manh, Thien P. Vu ; Dalod, Marc ; Lawrence, Toby

Conventional type 1 dendritic cells (cDC1s) perform specialized roles in antitumor immunity by processing and presenting tumor antigens that prime tumor-specific T cell responses. Using a mouse model of immunogenic tumor growth and single-cell transcriptomics, Ghislat et al. demonstrate that cDC1s require NF-κB signaling for their intratumoral maturation into antitumoral cDC1s capable of recruiting and activating tumor-specific T cells. IKKβ controlled the expression of IRF1, a transcription [...]

Cet article analyse le rôle du microbiote intestinal dans le développement de certains cancers de l'appareil digestif ainsi que l'efficacité et la toxicité des anticancéreux (inhibiteurs de point de contrôle immunitaire, chimiothérapies), examine l'effet des antibiotiques et autres médicaments sur ce microbiote puis présente les différentes stratégies thérapeutiques actuelles pour le réguler

The gut microbiome: what the oncologist ought to know

Lee, K. A. ; Luong, M. K. ; Shaw, H. ; Nathan, P. ; Bataille, V. ; Spector, T. D.

The gut microbiome (GM) has been implicated in a vast number of human pathologies and has become a focus of oncology research over the past 5 years. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation and protection against pathogens. Strong evidence is emerging to support the effects of the GM on the development of some malignancies but also on responses [...]

Cet article analyse les caractéristiques cliniques et génétiques des adénocarcinomes canalaires du pancréas avec mutation du gène BRCA1 ou BRCA2 puis passe en revue les stratégies thérapeutiques actuelles et celles en cours d'évaluation

BRCA-mutant pancreatic ductal adenocarcinoma

Lai, Eleonora ; Ziranu, Pina ; Spanu, Dario ; Dubois, Marco ; Pretta, Andrea ; Tolu, Simona ; Camera, Silvia ; Liscia, Nicole ; Mariani, Stefano ; Persano, Mara ; Migliari, Marco ; Donisi, Clelia ; Demurtas, Laura ; Pusceddu, Valeria ; Puzzoni, Marco ; Scartozzi, Mario

Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2—typically associated with breast and ovarian cancer—in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the [...]

Cet article passe en revue les connaissances concernant le métabolisme des cellules cancéreuses de la prostate

Metabolic reprogramming in prostate cancer

Ahmad, Fahim ; Cherukuri, Murali Krishna ; Choyke, Peter L.

Although low risk localised prostate cancer has an excellent prognosis owing to effective treatments, such as surgery, radiation, cryosurgery and hormone therapy, metastatic prostate cancer remains incurable. Existing therapeutic regimens prolong life; however, they are beset by problems of resistance, resulting in poor outcomes. Treatment resistance arises primarily from tumour heterogeneity, altered genetic signatures and metabolic reprogramming, all of which enable the tumour to serially [...]

Cet article analyse les caractéristiques immunobiologiques des cancers de la prostate et examine l'implication de ces caractéristiques dans la prise en charge thérapeutique et le pronostic

The therapeutic and prognostic implications of immunobiology in colorectal cancer: a review

Zaborowski, Alexandra M. ; Winter, Des C. ; Lynch, Lydia

Colorectal cancer represents the second leading cause of cancer-related death worldwide. The therapeutic field of immuno-oncology has rapidly gained momentum, with strikingly promising results observed in clinical practice. Increasing emphasis has been placed on the role of the immune response in tumorigenesis, therapy and predicting prognosis. Enhanced understanding of the dynamic and complex tumour-immune microenvironment has enabled the development of molecularly directed, individualised [...]