Menée à l'aide de lignées cellulaires ainsi que d'échantillons biopsiques prélevés sur des patients atteints d'un cancer gastrique ou d'une autre maladie de l'estomac, cette étude identifie au niveau du génome de la bactérie Helicobacter pylori un polymorphisme à simple nucléotide associé à la carcinogenèse

A single-nucleotide polymorphism in Helicobacter pylori promotes gastric cancer development

Sharafutdinov, Irshad ; Tegtmeyer, Nicole ; Linz, Bodo ; Rohde, Manfred ; Vieth, Michael ; Tay, Alfred Chin-Yen ; Lamichhane, Binit ; Tuan, Vo Phuoc ; Fauzia, Kartika Afrida ; Sticht, Heinrich ; Yamaoka, Yoshio ; Marshall, Barry J. ; Backert, Steffen

Single-nucleotide polymorphisms (SNPs) in various human genes are key factors in carcinogenesis. However, whether SNPs in bacterial pathogens are similarly crucial in cancer development is unknown. Here, we analyzed 1,043 genomes of the stomach pathogen Helicobacter pylori and pinpointed a SNP in the serine protease HtrA (position serine/leucine 171) that significantly correlates with gastric cancer. Our functional studies reveal that the 171S-to-171L mutation triggers HtrA trimer formation and [...]

Menée à l'aide de lignées cellulaires et de 3 modèles murins de carcinome hépatocellulaire métastatique, cette étude met en évidence un mécanisme par lequel l'ARN circulaire circASH2, en modifiant la structure du cytosquelette des cellules tumorales, inhibe le développement de métastases

Cytoskeleton remodeling mediated by circRNA-YBX1 phase separation suppresses the metastasis of liver cancer

Liu, Boqiang ; Shen, Hao ; He, Jing ; Jin, Binghan ; Tian, Yuanshi ; Li, Weiqi ; Hou, Lidan ; Zhao, Weijun ; Nan, Junjie ; Zhao, Jia ; Shen, Jiliang ; Yu, Hong ; Wang, Yifan ; Shan, Ge ; Shi, Liang ; Cai, Xiujun

Metastasis, especially intrahepatic, is a major challenge for hepatocellular carcinoma (HCC) treatment. Cytoskeleton remodeling has been identified as a vital process mediating intrahepatic spreading. Previously, we reported that HCC tumor adhesion and invasion were modulated by circular RNA (circRNA), which has emerged as an important regulator of various cellular processes and has been implicated in cancer progression. Here, we uncovered a nuclear circRNA, circASH2, which is preferentially [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel un dysfonctionnement de la cohésine, un complexe protéique impliqué dans la cohésion des chromatides soeurs durant la méiose et la mitose, favorise la tumorigenèse

Cohesin maintains replication timing to suppress DNA damage on cancer genes

Liu, Yang ; Zhang, Weiwei ; Wu, Jinchun ; Zhangding, Zhengrong ; Liu, Xuhao ; Ai, Chen ; Gan, Tingting ; Liang, Haoxin ; Guo, Yuefeng ; Chen, Mohan ; Liu, Yiyang ; Yin, Jianhang ; Hu, Jiazhi

Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism underlying its role in tumorigenesis is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks and 147 translocation hotspot genes, co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor disruption. However, damage-induced chromosomal translocations coincide [...]

Menée in vitro et à l'aide de deux modèles murins de cancer colorectal, cette étude met en évidence un mécanisme par lequel la bactérie Carnobacterium maltaromaticum, en augmentant la production intestinale de vitamine D, favorise la suppression tumorale

Carnobacterium maltaromaticum boosts intestinal vitamin D production to suppress colorectal cancer in female mice

Li, Qing ; Chan, Hung ; Liu, Wei-Xin ; Liu, Chang-An ; Zhou, Yunfei ; Huang, Dan ; Wang, Xueliang ; Li, Xiaoxing ; Xie, Chuan ; Liu, Wing Ying-Zhi ; Wang, Xian-Song ; Ng, Siu Kin ; Gou, Hongyan ; Zhao, Liu-Yang ; Fong, Winnie ; Jiang, Lanping ; Lin, Yufeng ; Zhao, Guijun ; Bai, Feihu ; Liu, Xiaodong ; Chen, Huarong ; Zhang, Lin ; Wong, Sunny Hei ; Chan, Matthew Tak Vai ; Wu, William Ka Kei ; Yu, Jun

Carnobacterium maltaromaticum was found to be specifically depleted in female patients with colorectal cancer (CRC). Administration of C. maltaromaticum reduces intestinal tumor formation in two murine CRC models in a female-specific manner. Estrogen increases the attachment and colonization of C. maltaromaticum via increasing the colonic expression of SLC3A2 that binds to DD-CPase of this bacterium. Metabolomic and transcriptomic profiling unveils the increased gut abundance of vitamin [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel des lésions épigénétiques peuvent favoriser la gliomagenèse

Modeling epigenetic lesions that cause gliomas

Rahme, Gilbert J. ; Javed, Nauman M. ; Puorro, Kaitlyn L. ; Xin, Shouhui ; Hovestadt, Volker ; Johnstone, Sarah E. ; Bernstein, Bradley E.

Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells [...]

Menée à partir d'échantillons de moelle osseuse et d'échantillons sanguins, cette étude analyse l'origine clonale de la transformation d'une leucémie lymphoblastique aiguë en leucémie myéloïde aiguë après un traitement par lymphocytes CAR-T anti-CD19 et blinatumomab

Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy

Coorens, Tim H. H. ; Collord, Grace ; Treger, Taryn D. ; Adams, Stuart ; Mitchell, Emily ; Newman, Barbara ; Getz, Gad ; Godfrey, Anna L. ; Bartram, Jack ; Behjati, Sam

Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias1–4 remains unresolved. Here, we reconstructed the phylogeny of multiple leukemias in a girl who, following multiply relapsed ALL, received anti-CD19 cellular and antibody treatment and subsequently developed AML. Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver [...]

Menée à l'aide de modèles murins et d'échantillons tumoraux provenant de patients atteints d'un adénocarcinome du poumon, cette étude met en évidence un mécanisme par lequel la phosphorylation et la translocation nucléaire de la protéine DICER1 favorisent l'ouverture de la chromatine et la plasticité des cellules alvéolaires AT2 cancéreuses

Phosphorylated nuclear DICER1 promotes open chromatin state and lineage plasticity of AT2 tumor cells in lung adenocarcinomas

Reyes-Castro, Raisa A. ; Chen, Shin-Yu ; Seemann, Jacob ; Kundu, Samrat T. ; Gibbons, Don L. ; Arur, Swathi

KRAS/ERK pathway phosphorylates DICER1, causing its nuclear translocation, and phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. While DICER1 canonically regulates microRNAs (miRNA) and epithelial-to-mesenchymal transition (EMT), we found that phosphorylated nuclear DICER1 (phospho–nuclear DICER1) promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. [...]

Cet article analyse le rôle des récepteurs PD-1 des lymphocytes T, passe en revue les principales données prouvant l'existence de tels récepteurs sur certaines cellules cancéreuses et examine les implications thérapeutiques associées

PD-1 receptor outside the main paradigm: tumour-intrinsic role and clinical implications for checkpoint blockade

Donini, C. ; Galvagno, F. ; Rotolo, R. ; Massa, A. ; Merlini, A. ; Scagliotti, G. V. ; Novello, S. ; Bironzo, P. ; Leuci, V. ; Sangiolo, D.

Blocking the inhibitory receptor PD-1 on antitumour T lymphocytes is the main rationale underlying the clinical successes of cancer immunotherapies with checkpoint inhibitor (CI) antibodies (Abs). Besides this main paradigm, there is recent evidence of unconventional and “ectopic” signalling pathways of PD-1, found to be expressed not only by lymphocytes but also by peculiar subsets of cancer cells. Several groups reported on the tumour-intrinsic role of PD-1 in multiple settings, including [...]

Menée à l'aide de modèles murins et d'échantillons de sang, d'ascites, de tumeurs, de métastases et de ganglions pelviens prélevés sur des patientes atteintes d'un cancer de l'ovaire, cette étude examine les caractéristiques immunitaires des ascites et met en évidence le rôle de ces dernières dans la modification de l'écosystème des tumeurs primitives et des métastases

Single-cell analyses implicate ascites in remodeling the ecosystems of primary and metastatic tumors in ovarian cancer

Zheng, Xiaocui ; Wang, Xinjing ; Cheng, Xi ; Liu, Zhaoyuan ; Yin, Yujia ; Li, Xiaoduan ; Huang, Zhihao ; Wang, Ziliang ; Guo, Wei ; Ginhoux, Florent ; Li, Ziyi ; Zhang, Zemin ; Wang, Xipeng

Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC ecosystem with five tumor-relevant sites, including omentum metastasis and malignant ascites. Our data reveal the potential roles of ascites-enriched memory T cells as a pool for tumor-infiltrating exhausted CD8+ T cells and T helper 1-like cells. Moreover, tumor-enriched macrophages exhibited a preference for monocyte-derived [...]

Menée à l'aide d'échantillons de tumeurs colorectales et de lésions pré-cancéreuses, cette étude met en évidence une corrélation entre le niveau de méthylation des promoteurs et des régions amplificatrices de l'ADN et l'expression des facteurs de transcription spécifiques aux cancers colorectaux

Transcription factor expression repertoire basis for epigenetic and transcriptional subtypes of colorectal cancers

Bhandari, Yuba R. ; Krishna, Vinod ; Powers, Rachael ; Parmar, Sehej ; Thursby, Sara-Jayne ; Gupta, Ekta ; Kulak, Ozlem ; Gokare, Prashanth ; Reumers, Joke ; Van Wesenbeeck, Liesbeth ; Bachman, Kurtis E. ; Baylin, Stephen B. ; Easwaran, Hariharan

Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by varying degrees of promoter DNA hypermethylation, and its relation to the transcriptional subtypes is not well understood. We link cancer-specific transcription factor (TF) expression alterations to methylation alterations near TF-binding sites at promoter and enhancer regions in CRCs and their premalignant precursor lesions to [...]

Menée à l'aide de modèles murins ainsi que d'échantillons fécaux provenant de 444 patients atteints d'un cancer colorectal et de 575 témoins sains, cette étude met en évidence un mécanisme par lequel la bactérie Roseburia intestinalis protège de la tumorigenèse et améliore l'efficacité des anti-PD1

Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8+ T cells

Xing, Kang ; Changan, Liu ; Yanqiang, Ding ; Yunbi, Ni ; Fenfen, Ji ; Harry Cheuk Hay, Lau ; Lanping, Jiang ; Joseph, J. Y. Sung ; Sunny, H. Wong ; Jun, Yu

Objective : Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy. Design : R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in ApcMin/+ or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft [...]

Menée à l'aide d'organoïdes ainsi que d'échantillons sanguins, d'échantillons de tissus mammaires normaux et d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude analyse l'évolution clonale des cellules mammaires, depuis l'acquisition d'altérations génétiques "conductrices" jusqu'au développement de la maladie

Evolutionary histories of breast cancer and related clones

Nishimura, Tomomi ; Kakiuchi, Nobuyuki ; Yoshida, Kenichi ; Sakurai, Takaki ; Kataoka, Tatsuki R. ; Kondoh, Eiji ; Chigusa, Yoshitsugu ; Kawai, Masahiko ; Sawada, Morio ; Inoue, Takuya ; Takeuchi, Yasuhide ; Maeda, Hirona ; Baba, Satoko ; Shiozawa, Yusuke ; Saiki, Ryunosuke ; Nakagawa, Masahiro M. ; Nannya, Yasuhito ; Ochi, Yotaro ; Hirano, Tomonori ; Nakagawa, Tomoe ; Inagaki-Kawata, Yukiko ; Aoki, Kosuke ; Hirata, Masahiro ; Nanki, Kosaku ; Matano, Mami ; Saito, Megumu ; Suzuki, Eiji ; Takada, Masahiro ; Kawashima, Masahiro ; Kawaguchi, Kosuke ; Chiba, Kenichi ; Shiraishi, Yuichi ; Takita, Junko ; Miyano, Satoru ; Mandai, Masaki ; Sato, Toshiro ; Takeuchi, Kengo ; Haga, Hironori ; Toi, Masakazu ; Ogawa, Seishi

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1–3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique [...]