Menée in vitro et à l'aide de modèles murins de carcinome épidermoïde du poumon, cette étude met en évidence un mécanisme par lequel l'amplification ou un variant du gène de la méthyltransférase NSD3 favorise la tumorigenèse en augmentant la méthylation de la lysine 36 de l'histone H3

Elevated NSD3 histone methylation activity drives squamous cell lung cancer

Yuan, Gang ; Flores, Natasha M. ; Hausmann, Simone ; Lofgren, Shane M. ; Kharchenko, Vladlena ; Angulo-Ibanez, Maria ; Sengupta, Deepanwita ; Lu, Xiaoyin ; Czaban, Iwona ; Azhibek, Dulat ; Vicent, Silvestre ; Fischle, Wolfgang ; Jaremko, Mariusz ; Fang, Bingliang ; Wistuba, Ignacio I. ; Chua, Katrin F. ; Roth, Jack A. ; Minna, John D. ; Shao, Ning-Yi ; Jaremko, Łukasz ; Mazur, Pawel K. ; Gozani, Or

Amplification of chromosomal region 8p11–12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)1–3. The FGFR1 gene is the main candidate driver of tumorigenesis within this region4. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful5. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11–12 amplicon, as a key regulator of LUSC [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'oncoprotéine CREPT (autre nom de la protéine RPRD1B), en interagissant avec le facteur de transcription STAT3 phosphorylé et en facilitant le recrutement de P300 (une acétyltransférase impliquée dans la transcription des gènes ciblés par STAT3), favorise la tumorigenèse

CREPT/RPRD1B promotes tumorigenesis through STAT3-driven gene transcription in a p300-dependent manner

Zhai, Wanli ; Ye, Xiongjun ; Wang, Yinyin ; Feng, Yarui ; Wang, Ying ; Lin, Yuting ; Ding, Lidan ; Yang, Liu ; Wang, Xuning ; Kuang, Yanshen ; Fu, Xinyuan ; Eugene Chin, Y. ; Jia, Baoqing ; Zhu, Bingtao ; Ren, Fangli ; Chang, Zhijie

Background : Signal transducer and activator of transcription 3 (STAT3) has been shown to upregulate gene transcription during tumorigenesis. However, how STAT3 initiates transcription remains to be exploited. This study is to reveal the role of CREPT (cell cycle-related and elevated-expression protein in tumours, or RPRD1B) in promoting STAT3 transcriptional activity. Methods : BALB/c nude mice, CREPT overexpression or deletion cells were employed for the assay of tumour formation, chromatin [...]

Menée in vitro et à l'aide de modèles murins modifiés génétiquement, cette étude met en évidence un mécanisme par lequel la paraoxonase PON2, en interagissant avec un inhibiteur du transport de glucose, favorise la leucémogenèse

PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis

Pan, Lili ; Hong, Chao ; Chan, Lai N. ; Xiao, Gang ; Malvi, Parmanand ; Robinson, Mark E. ; Geng, Huimin ; Reddy, Srinivasa T. ; Lee, Jaewoong ; Khairnar, Vishal ; Cosgun, Kadriye Nehir ; Xu, Liang ; Kume, Kohei ; Sadras, Teresa ; Wang, Shaoyuan ; Wajapeyee, Narendra ; Müschen, Markus

B lymphoid transcription factors (e.g., IKZF1 and PAX5) not only mediate B cell lineage commitment but also repress glucose transport and energy supply, thus acting as metabolic gatekeepers. While previous studies showed regulation of metabolic gatekeeper functions at the transcriptional level, we here discovered a mechanism of regulation based on protein–protein interactions between PON2 and the glucose-transport inhibitor stomatin (STOM).Unlike other cell types, developing B cells undergo [...]

Cet article analyse la contribution des voies de synthèse de la glycine et de la sérine dans la progression tumorale, le potentiel immunosuppresseur de ces deux acides-aminés puis examine l'intérêt de petites molécules pour cibler la synthèse de ces derniers

The ins and outs of serine and glycine metabolism in cancer

Geeraerts, Shauni L. ; Heylen, Elien ; De Keersmaecker, Kim ; Kampen, Kim R.

Cancer cells reprogramme their metabolism to support unrestrained proliferation and survival in nutrient-poor conditions. Whereas non-transformed cells often have lower demands for serine and glycine, several cancer subtypes hyperactivate intracellular serine and glycine synthesis and become addicted to de novo production. Copy-number amplifications of serine- and glycine-synthesis genes and genetic alterations in common oncogenes and tumour-suppressor genes enhance serine and glycine [...]

Menée à partir d'échantillons de tissus pulmonaires sains, d'échantillons de nodules pulmonaires de signification indéterminée et d'échantillons d'adénocarcinomes du poumon, cette étude analyse l'évolution du profil de méthylation de l'ADN au cours de la transformation de lésions pulmonaires précancéreuses en adénocarcinome invasif du poumon

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

Hu, Xin ; Estecio, Marcos R. ; Chen, Runzhe ; Reuben, Alexandre ; Wang, Linghua ; Fujimoto, Junya ; Carrot-Zhang, Jian ; McGranahan, Nicholas ; Ying, Lisha ; Fukuoka, Junya ; Chow, Chi-Wan ; Pham, Hoa H. N. ; Godoy, Myrna C. B. ; Carter, Brett W. ; Behrens, Carmen ; Zhang, Jianhua ; Antonoff, Mara B. ; Sepesi, Boris ; Lu, Yue ; Pass, Harvey I. ; Kadara, Humam ; Scheet, Paul ; Vaporciyan, Ara A. ; Heymach, John V. ; Wistuba, Ignacio I. ; Lee, J. Jack ; Futreal, P. Andrew ; Su, Dan ; Issa, Jean-Pierre J. ; Zhang, Jianjun

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. [...]

Menée à partir de données du projet "The Cancer Genome Atlas", de lignées cellulaires, d'échantillons tumoraux et de modèles murins de glioblastome multiforme, cette étude met en évidence le rôle des ligands CXCL1 et CXCL2 dans l'immunosuppression tumorale et la survie des cellules cancéreuses

Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme

Hu, Jiemiao ; Zhao, Qingnan ; Kong, Ling-Yuan ; Wang, Jian ; Yan, Jun ; Xia, Xueqing ; Jia, Zhiliang ; Heimberger, Amy B. ; Li, Shulin

The invasiveness and high immune suppression of glioblastoma multiforme (GBM) produce poor survival of afflicted patients. Unfortunately, in the past decades, no therapeutic approach has remarkably improved the survival time of patients with GBM. Our analysis of the TCGA database and brain tumor tissue arrays indicated that CXCL1 and CXCL2 overexpression is closely associated with GBM’s aggressiveness. Our results showed that elevation of CXCL1 or CXCL2 facilitated myeloid cell migration and [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la désacétylation de la nucléophosmine via la sirtuine 7 favorise la stabilisation de la protéine p53 après un stress génotoxique induit par les ultraviolets

SIRT7-dependent deacetylation of NPM promotes p53 stabilization following UV-induced genotoxic stress

Ianni, Alessandro ; Kumari, Poonam ; Tarighi, Shahriar ; Simonet, Nicolas G. ; Popescu, Daniela ; Guenther, Stefan ; Hölper, Soraya ; Schmidt, Andreas ; Smolka, Christian ; Yue, Shijing ; Krüger, Marcus ; Fiorillo, Claudia ; Vaquero, Alejandro ; Bober, Eva ; Braun, Thomas

We discovered that the histone/protein deacetylase SIRT7, which is the only member of the mammalian sirtuin family residing primarily in the nucleolus, stabilizes p53 in response to UV-induced DNA damage by enabling binding of deacetylated NPM to MDM2/HDM2. The study unveils a crucial mechanism by which the nucleolus controls cellular stress responses. Furthermore, it characterizes SIRT7 as a potent regulator of cellular stress and offers opportunities to manipulate cellular p53 levels, which [...]

Menée à partir de données de séquençage portant sur environ 10 000 échantillons tumoraux d'origine humaine et 600 lignées cellulaires, cette étude démontre que le doublement du génome des cellules cancéreuses confère à ces dernières des vulnérabilités spécifiques suggérant de nouvelles stratégies thérapeutiques

Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Quinton, Ryan J. ; DiDomizio, Amanda ; Vittoria, Marc A. ; Kotýnková, Kristýna ; Ticas, Carlos J. ; Patel, Sheena ; Koga, Yusuke ; Vakhshoorzadeh, Jasmine ; Hermance, Nicole ; Kuroda, Taruho S. ; Parulekar, Neha ; Taylor, Alison M. ; Manning, Amity L. ; Campbell, Joshua D. ; Ganem, Neil J.

Whole-genome doubling (WGD) is common in human cancers, occurring early in tumorigenesis and generating genetically unstable tetraploid cells that fuel tumour development1,2. Cells that undergo WGD (WGD+ cells) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can be exploited therapeutically, is unclear. Here, using sequencing data from roughly 10,000 primary human cancer samples and essentiality [...]

Menée à partir de données portant sur 66 patients atteints d'un adénocarcinome canalaire du pancréas, cette étude identifie les caractéristiques cliniques des patients présentant des altérations au niveau du gène ATM

Clinical Characteristics of Patients with Pancreatic Cancer and Pathogenic ATM Alterations

Hannan, Zain ; Yu, Shun ; Domchek, Susan ; Mamtani, Ronac ; Reiss, Kim A.

The Ataxia-Telangiesctasia mutated (ATM) gene is involved in a number of DNA damage repair pathways and confers an increased risk for pancreatic ductal adenocarcinoma (PDAC). In this retrospective study, we identified and profiled 22 patients with PDAC and a known somatic or germline pathogenic ATM alteration (cases). These patients were matched 2:1 by age, stage and year at diagnosis to patients with PDAC patients without known ATM alterations. The median overall survival in patients with ATM [...]

Menée à l'aide de lignées cellulaires et d'un modèle murin d'adénocarcinome canalaire du pancréas, cette étude met en évidence le rôle de l'autophagie dans la régulation du transporteur de la cystéine SLC7A11 et le métabolisme de cet acide aminé

Autophagy is required for proper cysteine homeostasis in pancreatic cancer through regulation of SLC7A11

Mukhopadhyay, Subhadip ; Biancur, Douglas E. ; Parker, Seth J. ; Yamamoto, Keisuke ; Banh, Robert S. ; Paulo, Joao A. ; Mancias, Joseph D. ; Kimmelman, Alec C.

Pancreatic cancer utilizes autophagy to survive stress and promote therapeutic resistance. However, the metabolic contribution of autophagy in PDAC has not been fully elucidated. We report that SLC7A11 function requires autophagy machinery for proper membrane localization in PDAC, allowing proper cystine transport. Our findings continue to support the use of autophagy inhibition as a therapeutic strategy in pancreatic cancer by demonstrating that this leads to inactivation of SLC7A11 and [...]

Menée sur des lignées de lymphocytes B et de cellules prostatiques, cette étude met en évidence un mécanisme par lequel la surexpression de Myc modifie fortement le niveau d'expression des protéines de surface

Large remodeling of the Myc-induced cell surface proteome in B cells and prostate cells creates new opportunities for immunotherapy

Chen, Wentao ; Mou, Kurt Yun ; Solomon, Paige ; Aggarwal, Rahul ; Leung, Kevin K. ; Wells, James A.

MYC is a powerful transcription factor overexpressed in many human cancers including B cell and prostate cancers. Antibody therapeutics are exciting opportunities to attack cancers but require knowledge of surface proteins that change due to oncogene expression. To identify how MYC overexpression remodels the cell surface proteome in a cell autologous fashion and in different cell types, we investigated the impact of MYC overexpression on 800 surface proteins in three isogenic model cell lines [...]