Menée in vitro et à l'aide de modèles murins, cette étude démontre que l'excès de sous-unités p50 du facteur NF-kappaB favorise la suppression des tumeurs via des mécanismes induits par le ligand PD-L1 et des chimiokines

Excess of the NF-ĸB p50 subunit generated by the ubiquitin ligase KPC1 suppresses tumors via PD-L1– and chemokines-mediated mechanisms

Pikarsky, Eli ; Kravtsova-Ivantsiv, Yelena ; Goldhirsh, Gilad ; Ivantsiv, Alexandra ; Ben Itzhak, Ofer ; Kwon, Yong Tae ; Ciechanover, Aaron

Recruitment of the immune system to suppress malignant tumors can involve different mechanisms, including inhibition of suppressive immune checkpoints (the enemy of my enemy is my friend), generation of specific CAR-T cells that recognize tumor cells, and immunization against the patient’s tumor antigens. Here we describe a mechanism, where excess of the p50 subunit of the NF-ĸB transcription factor that when pairs with another subunit—p65—is oncogenic, but when generated in excess over p65 and [...]

Menée in vitro et à l'aide de xénogreffes de cellules leucémiques sur des modèles murins, cette étude met en évidence un mécanisme par lequel la protéine BAHCC1, en liant la lysine 27 triméthylée de l'histone H3 (H3K27me3) via le domaine BAH, favorise la répression des gènes et l'oncogenèse

BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis

Fan, Huitao ; Lu, Jiuwei ; Guo, Yiran ; Li, Dongxu ; Zhang, Zhi-Min ; Tsai, Yi-Hsuan ; Pi, Wen-Chieh ; Ahn, Jeong Hyun ; Gong, Weida ; Xiang, Yu ; Allison, David F. ; Geng, Huimin ; He, Shenghui ; Diao, Yarui ; Chen, Wei-Yi ; Strahl, Brian D. ; Cai, Ling ; Song, Jikui ; Wang, Gang Greg

Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) ‘recognizes’ H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic [...]

Menée à l'aide d'échantillons de moelle osseuse et d'échantillons sanguins issus de patients atteints d'une leucémie aigüe lymphoblastique à lymphocytes B et menée à l'aide de modèles murins, cette étude met en évidence le rôle de la protéine transmembranaire IFITM3 dans l'amplification de la signalisation des kinases PI3K des lymphocytes B

IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells

Lee, Jaewoong ; Robinson, Mark E. ; Ma, Ning ; Artadji, Dewan ; Ahmed, Mohamed A. ; Xiao, Gang ; Sadras, Teresa ; Deb, Gauri ; Winchester, Janet ; Cosgun, Kadriye Nehir ; Geng, Huimin ; Chan, Lai N. ; Kume, Kohei ; Miettinen, Teemu P. ; Zhang, Ye ; Nix, Matthew A. ; Klemm, Lars ; Chen, Chun Wei ; Chen, Jianjun ; Khairnar, Vishal ; Wiita, Arun P. ; Thomas-Tikhonenko, Andrei ; Farzan, Michael ; Jung, Jae U. ; Weinstock, David M. ; Manalis, Scott R. ; Diamond, Michael S. ; Vaidehi, Nagarajan ; Müschen, Markus

Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1–3. Here we studied clinical cohorts of patients with B cell leukaemia and lymphoma, and identified IFITM3 as a strong predictor of poor outcome. In normal resting B cells, IFITM3 was minimally expressed and mainly localized in endosomes. However, engagement of the B cell receptor (BCR) induced both expression of IFITM3 and phosphorylation of this protein at [...]

Menée sur des lignées cellulaires de carcinome hépatocellulaire et sur des rats, cette étude met en évidence un mécanisme par lequel le facteur de croissance EGF, en augmentant la phosphorylation et l'acétylation de l'histone H3, favorise la transcription de DKK1, un gène impliqué dans la progression métastatique

EGF promotes DKK1 transcription in hepatocellular carcinoma by enhancing the phosphorylation and acetylation of histone H3

Niu, Jie ; Li, Wei ; Liang, Chao ; Wang, Xiao ; Yao, Xin ; Yang, Ruo-Han ; Zhang, Zhan-Sheng ; Liu, Han-Fang ; Liu, Fan-Ye ; Pei, Shu-Hua ; Li, Wen-Qi ; Sun, Hua ; Fang, Dong ; Xie, Song-Qiang

Hepatocellular carcinoma (HCC) is a common form of liver cancer. The Wnt signaling protein DKK1 and the growth factor receptor EGFR are abundant in HCC and are associated with metastatic progression and poor prognosis in patients. Niu et al. found that these molecular markers are linked. The activation of EGFR in HCC cells induced DKK1 expression through parallel pathways: MEK-ERK pathway–dependent nuclear translocation of the kinase PKM2 and PI3K-AKT pathway–dependent activation of the [...]

Menée à partir du séquençage de l'ensemble de l'exome de tissus tumoraux et d'échantillons sanguins prélevés sur 26 patients atteints d'un adénocarcinome pulmonaire, cette étude compare les caractéristiques mutationnelles des lésions primitives avec celles des métastases hépatiques et des métastases cérébrales, puis compare l'évolution génétique de ces deux types de métastases

Mutational landscape and evolutionary pattern of liver and brain metastasis in lung adenocarcinoma

Jiang, Tao ; Fang, Zhaoyuan ; Tang, Shijie ; Cheng, Ruirui ; Li, Yanan ; Ren, Shengxiang ; Su, Chunxia ; Min, Weijie ; Guo, Xianchao ; Zhu, Wei ; Zhang, Henghui ; Hou, Likun ; Pan, Yuanwei ; Zhou, Zhigang ; Zhang, Jun ; Zhang, Guojun ; Yue, Zhijian ; Chen, Luonan ; Zhou, Caicun

Introduction : Comprehensive genomic analysis of paired primary tumors and their metastatic lesions may provide new insights into the biology of metastatic processes and therefore guide the development of novel strategies for intervention. To date, our knowledge of the genetic divergence and phylogenetic relationships among diverse metastatic lesions from one cancer remains limited. Methods : Here, we performed whole-exome sequencing in 84 tissue and blood samples from 26 lung adenocarcinoma [...]

Menée à l'aide de cellules souches neuronales de souris, cette étude démontre que les cellules souches de glioblastome induisent la quiescence des cellules souches neuronales environnantes via la voie de signalisation de Notch

Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signaing

Lawlor, Katerina ; Marques-Torrejon, Maria Angeles ; Dharmalingham, Gopuraja ; El-Azhar, Yasmine ; Schneider, Michael D. ; Pollard, Steven M. ; Rodríguez, Tristan A.

There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell–cell contact and Notch signaling-dependent manner. Our findings [...]

Cet article analyse le rôle du facteur de transcription TCF1 dans la régulation de la réponse des lymphocytes T durant les phases inflammatoires induites par certaines maladies, en particulier les maladies autoimmunes, les infections chroniques et les cancers

T cell factor 1: A master regulator of the T cell response in disease

Escobar, Giulia ; Mangani, Davide ; Anderson, Ana C.

Recent advances have redefined a role for T cell factor 1 (TCF1) that goes beyond T cell development and T memory formation and encompasses new functions in the regulation of T cell biology. Here, we discuss the multifaceted and context-dependent role of TCF1 in peripheral T cells, particularly during disease-induced inflammatory states such as autoimmunity, cancer, and chronic infections. Understanding how TCF1 fine-tunes peripheral T cell biology holds the potential to tailor improved [...]

Cet article présente un algorithme, utilisant des données génétiques et épigénétiques, pour découvrir des oncogènes et des gènes suppresseurs de tumeurs

DORGE: Discovery of Oncogenes and tumoR suppressor genes using Genetic and Epigenetic features

Lyu, Jie ; Li, Jingyi Jessica ; Su, Jianzhong ; Peng, Fanglue ; Chen, Yiling Elaine ; Ge, Xinzhou ; Li, Wei

Data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. Here, we developed an algorithm, DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), to identify TSGs and OGs by integrating [...]

Menée à partir de l'analyse de l'ADN des globules blancs de 325 patientes chinoises atteintes d'un cancer du sein triple négatif, cette étude identifie des variants constitutionnels puis détermine leurs caractéristiques moléculaires et leurs implications fonctionnelles

Molecular features and functional implications of germline variants in triple-negative breast cancer

Ma, Ding ; Chen, Si-Yu ; Ren, Jin-Xiao ; Pei, Yu-Chen ; Jiang, Cong-Wei ; Zhao, Shen ; Xiao, Yi ; Xu, Xiao-En ; Liu, Guang-Yu ; Hu, Xin ; Liang, Xiao-Zhen ; Yu, Ke-Da ; Li, Da-Qiang ; Jiang, Yi-Zhou ; Shao, Zhi-Ming

The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among Chinese patients and its clinical significance remain unclear.Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications.Overall, 16.0% (52 of 325) of TNBC patients harbored at least one [...]