Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel la perte d'expression des dioxygénases TET favorise le développement d'un cancer du poumon en modifiant la signalisation des glycoprotéines Wnt via l'altération du processus de déméthylation

Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development

Xu, Qin ; Wang, Chao ; Zhou, Jia-Xin ; Xu, Zhi-Mei ; Gao, Juan ; Sui, Pengfei ; Walsh, Colum P. ; Ji, Hongbin ; Xu, Guo-Liang

Oncogenic imbalance of DNA methylation is well recognized in cancer development. The ten-eleven translocation (TET) family of dioxygenases, which facilitates DNA demethylation, is frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here, we identify loss-of-function mutations of TET in 7.4% of human lung adenocarcinoma (LUAD), which frequently [...]

Cet article passe en revue les connaissances concernant le mécanisme par lequel les tumeurs, en réveillant un programme embryonnaire de vascularisation, échappent au système immunitaire

Tumors resurrect an embryonic vascular program to escape immunity

Huijbers Elisabeth, J. M. ; Khan Kabir, A. ; Kerbel Robert, S. ; Griffioen Arjan, W.

Tumors can escape immunity through multiple mechanisms, one of which is by enforcing a state of unresponsiveness of the tumor vasculature to inflammatory cytokines. This results in a lack of adhesiveness of angiogenic endothelial cells for immune cells and thus compromised immunity. This type of escape from immunity, called tumor endothelial cell anergy, is the result of exposure to angiogenic growth factors. Angiogenesis is a hallmark not only of cancer but also of embryonic development. It is [...]

Menée in vitro et à l'aide de modèles murins de leucémie myéloïde chronique, cette étude démontre que la perte de l'expression du microARN miR-31-5p favorise la transformation maligne des cellules souches hématopoïétiques et que la restauration de son expression élimine les cellules souches leucémiques

Loss of miR-31-5p drives hematopoietic stem cell malignant transformation and restoration eliminates leukemia stem cells in mice

Biying Zhu ; Wenbin Zhong ; Xiuye Cao ; Guoping Pan ; Mengyang Xu ; Jie Zheng ; Huanzhao Chen ; Xiaoqin Feng ; Chengwei Luo ; Chen Lu ; Jie Xiao ; Weize Lin ; Chaofeng Lai ; Mingchuan Li ; Xin Du ; Qing Yi ; Daoguang Yan

Leukemia stem cells (LSCs) originate from hematopoietic stem cells (HSCs), but our understanding of this transformation is limited. Here, Zhu and colleagues identified the microRNA miR-31-5p as a controller of the mode of energy metabolism in HSCs: Loss of miR-31-5p led to a transition away from glycolytic metabolism to oxidative phosphorylation, accumulation of the oncometabolite fumarate, and development of LSCs, whereas ectopic expression of miR-31-5p could eliminate LSCs. Treatment with [...]

Menée in vitro et à l'aide de xénogreffes de mélanomes sur des modèles murins, cette étude démontre que l'altération de la voie des pentoses phosphate, liée à une perte de la fonction de la glucose-6-phosphate déshydrogénase, est compensée par l'augmentation de la glutaminolyse et de l'activité de l'enzyme malique durant le processus métastatique

Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells

Aurora, Arin B. ; Khivansara, Vishal ; Leach, Ashley ; Gill, Jennifer G. ; Martin-Sandoval, Misty ; Yang, Chendong ; Kasitinon, Stacy Y. ; Bezwada, Divya ; Tasdogan, Alpaslan ; Gu, Wen ; Mathews, Thomas P. ; Zhao, Zhiyu ; DeBerardinis, Ralph J. ; Morrison, Sean J.

Melanoma metastasis is limited by oxidative stress. Cells that enter the blood experience high levels of reactive oxygen species and usually die of ferroptosis. We found that melanoma cells become more dependent upon the oxidative pentose phosphate pathway to manage oxidative stress during metastasis. When pentose phosphate pathway function was impaired by reduced glucose 6-phosphate dehydrogenase (G6PD) function, melanoma cells increased malic enzyme activity and glutamine consumption. [...]

Menée à l'aide de lignées cellulaires d'adénocarcinome canalaire du pancréas, d'organoïdes et de modèles murins, cette étude met en évidence un mécanisme par lequel les cellules cancéreuses, en interagissant directement avec les cellules étoilées du pancréas, peuvent lever les contraintes imposées par les réactions d'oxydo-réduction pour mieux proliférer

Interactions with stromal cells promote a more oxidized cancer cell redox state in pancreatic tumors

Datta, Rupsa ; Sivanand, Sharanya ; Lau Allison, N. ; Florek Logan, V. ; Barbeau Anna, M. ; Wyckoff, Jeffrey ; Skala Melissa, C. ; Vander Heiden Matthew, G.

Access to electron acceptors supports oxidized biomass synthesis and can be limiting for cancer cell proliferation, but how cancer cells overcome this limitation in tumors is incompletely understood. Nontransformed cells in tumors can help cancer cells overcome metabolic limitations, particularly in pancreatic cancer, where pancreatic stellate cells (PSCs) promote cancer cell proliferation and tumor growth. However, whether PSCs affect the redox state of cancer cells is not known. By taking [...]

Menée à l'aide de lignées cellulaires, d'un modèle murin ainsi que de tissus tumoraux et de tissus adjacents prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel la protéine iASPP, en supprimant la dégradation de la protéine TMCO1 induite par le récepteur du facteur autocrine de motilité Gp78, réduit le stockage de Ca2+ dans le réticulum endoplasmique et favorise la croissance tumorale ainsi que la résistance thérapeutique

iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca2+ homeostasis and control tumor growth and drug resistance

Zheng, Shanliang ; Zhao, Dong ; Hou, Guixue ; Zhao, Song ; Zhang, Wenxin ; Wang, Xingwen ; Li, Li ; Lin, Liang ; Tang, Tie-Shan ; Hu, Ying

Accumulating preclinical and clinical evidence has supported a central role for alterations in Ca2+ homeostasis in the development of cancer. TMCO1 protein is an identified Ca2+-channel protein, while its roles in cancer remain obscure. Here, we found that TMCO1 is increased in colon cancer tissues. In addition, it is a substrate of E3 ligase Gp78. Enhanced oncogene iASPP stabilizes TMCO1 by competitively binding with Gp78. Inhibition of iASPP-TMCO1 sensitizes cancer cells’ response to [...]

Menée in vitro et à l'aide de modèles murins de cancer mammaire, cette étude met en évidence un mécanisme par lequel la protéine CECR2 dirige le processus métastatique en favorisant la voie de signalisation du facteur nucléaire NF-kappa

CECR2 drives breast cancer metastasis by promoting NF-KappaB signaling and macrophage-mediated immune suppression

Zhang, Meiling ; Liu Zongzhi, Z. ; Aoshima, Keisuke ; Cai Wesley, L. ; Sun, Hongyin ; Xu, Tianrui ; Zhang, Yangyi ; An, Yongyan ; Chen Jocelyn, F. ; Chan Lok, Hei ; Aoshima, Asako ; Lang Sabine, M. ; Tang, Zhenwei ; Che, Xuanlin ; Li, Yao ; Rutter Sara, J. ; Bossuyt, Veerle ; Chen, Xiang ; Morrow Jon, S. ; Pusztai, Lajos ; Rimm David, L. ; Yin, Mingzhu ; Yan, Qin

Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 [...]

Menée à l'aide d'échantillons de tissus sains, de tumeurs bénignes, de cancer du poumon non à petites cellules ou de cancer du foie, cette étude met en évidence l'intérêt, pour la recherche sur les mécanismes moléculaires et le diagnostic en cancérologie, d'une méthode histologique utilisant un dispositif comportant un appareil photographique, un microscope optique, un aimant, une lame histologique, un laser vert et un diamant dont les centres azote-lacune (type de défaut dans la structure cristalline) permettent la détection des signaux magnétiques

Immunomagnetic microscopy of tumor tissues using quantum sensors in diamond

Chen, Sanyou ; Li, Wanhe ; Zheng, Xiaohu ; Yu, Pei ; Wang, Pengfei ; Sun, Ziting ; Xu, Yao ; Jiao, Defeng ; Ye, Xiangyu ; Cai, Mingcheng ; Shen, Mengze ; Wang, Mengqi ; Zhang, Qi ; Kong, Fei ; Wang, Ya ; He, Jie ; Wei, Haiming ; Shi, Fazhan ; Du, Jiangfeng

Understanding cancer’s biomarker, microenvironment, and heterogeneity at the tissue level promises to improve cancer biology and clinical diagnosis and treatment. Many histological imaging techniques have been developed for this purpose. In this study, benefiting from the development of quantum sensing with nitrogen-vacancy (NV) centers in diamond, we proposed and experimentally realized micrometer-resolution magnetic imaging of tumor tissues in an NV-diamond magnetic microscope, magnetically [...]

Menée à l'aide de la cristallographie, cette étude identifie la structure et la fonction du domaine effecteur de SAMD9 et SAMD9L, deux protéines impliquées dans la réponse immunitaire innée contre certains virus et le développement de tumeurs myéloïdes

Structure and function of an effector domain in antiviral factors and tumor suppressors SAMD9 and SAMD9L

Peng, Shuxia ; Meng, Xiangzhi ; Zhang, Fushun ; Pathak, Prabhat Kumar ; Chaturvedi, Juhi ; Coronado, Jaime ; Morales, Marisol ; Mao, Yuanhui ; Qian, Shu-Bing ; Deng, Junpeng ; Xiang, Yan

SAMD9 and SAMD9L (SAMD9/9L) are important innate immune defenders against viruses and the development of myeloid tumors. They form a crucial host barrier that poxviruses must overcome for successful infection. A myriad of human diseases including many pediatric myelodysplastic syndromes are caused by mutations in SAMD9/9L. However, the molecular functions of SAMD9/9L and how their functions are executed are unknown, hindering progress in developing effective therapies for SAMD9/9L-associated [...]

Menée à l'aide de lignées cellulaires de neuroblastome et de xénogreffes sur un modèle murin, cette étude met en évidence un lien entre les états épigénétiques des cellules cancéreuses et la signalisation inflammatoire

Epigenetic state determines inflammatory sensing in neuroblastoma

Wolpaw, Adam J. ; Grossmann, Liron D. ; Dessau, Jessica L. ; Dong, May M. ; Aaron, Bailey J. ; Brafford, Patricia A. ; Volgina, Darya ; Pascual-Pasto, Guillem ; Rodriguez-Garcia, Alba ; Uzun, Yasin ; Arsenian-Henriksson, Marie ; Powell, Daniel J. ; Bosse, Kristopher R. ; Kossenkov, Andrew ; Tan, Kai ; Hogarty, Michael D. ; Maris, John M. ; Dang, Chi V.

Making immunotherapy more widely effective requires improved understanding of the pathways that regulate the interactions between tumor and immune cells. This work identified a previously unappreciated difference in these pathways between heterogenous epigenetic states that coexist in neuroblastoma. The generally rarer mesenchymal subpopulation has more active inflammatory sensing and signaling, revealing a potential immunologic vulnerability of these chemotherapy-resistant cells. Immunotherapy [...]

Menée à l'aide d'un modèle murin transgénique de cancer de la trompe de Fallope, cette étude met en évidence l'inhibition de la carcinogenèse par un progestatif

Progestin Significantly Inhibits Carcinogenesis in the Mogp-TAg Transgenic Mouse Model of Fallopian Tube Cancer

Nelson, Omar L. ; Rosales, Rebecca ; Turbov, Jane M. ; Thaete, Larry G. ; Cline, J. Mark ; Rodriguez, Gustavo C.

Recent studies suggest that the fallopian tube epithelium (FTE) harbors the precursor for high-grade ovarian cancer, creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE is not well characterized. The murine oviduct–specific glycoprotein promotor-driven simian virus 40 large T-Antigen (mogp-TAg) transgenic mouse model develops neoplastic lesions in the fallopian [...]

Menée à partir de données du projet "The Cancer Genome Atlas" portant sur 965 échantillons de carcinomes du poumon non à petites cellules et menée à l'aide d'un logiciel utilisant l'intelligence artificielle, cette étude identifie les profils mutationnels et immunologiques des phénotypes immunitaires du microenvironnement tumoral

Artificial Intelligence-Powered H and E Analyzer Reveals Distinct Immunologic and Mutational Profiles Among Immune Phenotypes in Non-Small Cell Lung Cancer

Park, Jonghanne ; Cho, Hyung-Gyo ; Park, Jewel ; Lee, Grace ; Kim, Hye Sung ; Paeng, Kyunghyun ; Song, Sanghoon ; Park, Gahee ; Ock, Chan-Young ; Chae, Young Kwang

The tumor microenvironment can be classified into three immune phenotypes: inflamed, immune-excluded, and immune-desert. Immunotherapy efficacy has been shown to vary by phenotype; yet, the mechanisms are poorly understood and demands further investigation. In this study, we unveil the mechanisms using an artificial intelligence-powered software called Lunit SCOPE. We utilized the artificial intelligence to classify 965 samples of non-small cell lung carcinoma from The Cancer Genome Atlas into [...]

Menée in vitro et à l'aide d'un modèle murin de cancer colorectal associé à une colite, cette étude met en évidence un mécanisme par lequel l'aspirine, en réduisant notamment l'expression de PD1 sur les macrophages et les lymphocytes T CD8+, prévient la carcinogenèse

Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer

De Matteis, Roberta ; Flak Magdalena, B. ; Gonzalez-Nunez, Maria ; Austin-Williams, Shani ; Palmas, Francesco ; Colas Romain, A. ; Dalli, Jesmond

Inflammation is linked with carcinogenesis in many types of cancer including colorectal cancer (CRC). Aspirin is recommended for the prevention of CRC, although the mechanism(s) mediating its immunomodulatory actions remain incompletely understood. Here, we demonstrate that aspirin increased concentrations of the immune-regulatory aspirin-triggered specialized proresolving mediators (AT-SPMs), including AT-lipoxin A4 and AT-resolvin D1, in colonic tissues during inflammation-associated CRC [...]

Cet article passe en revue les connaissances concernant les mécanismes biologiques et moléculaires associant le microbiote intestinal à certaines maladies dont différents types de cancer

Gut microbiome and health: mechanistic insights

de Vos, Willem M. ; Tilg, Herbert ; Van Hul, Matthias ; Cani, Patrice D.

The gut microbiota is now considered as one of the key elements contributing to the regulation of host health. Virtually all our body sites are colonised by microbes suggesting different types of crosstalk with our organs. Because of the development of molecular tools and techniques (ie, metagenomic, metabolomic, lipidomic, metatranscriptomic), the complex interactions occurring between the host and the different microorganisms are progressively being deciphered. Nowadays, gut microbiota [...]

Menée à partir de données génétiques portant sur 1 752 patients atteints précocement d'un cancer colorectal, cette étude analyse les profils génomiques en fonction de l'origine ethnique

Racial and Ethnic Differences in Genomic Profiling of Early-Onset Colorectal Cancer

Hein, David M. ; Deng, Weiye ; Bleile, MaryLena ; Kazmi, Syed Ali ; Rhead, Brooke ; De La Vega, Francisco M. ; Jones, Amy L. ; Kainthla, Radhika ; Jiang, Wen ; Cantarel, Brandi ; Sanford, Nina N.

The incidence and mortality of early-onset colorectal cancer (EOCRC) are rising; outcomes appear to differ by race and ethnicity. We aimed to assess differences in mutational landscape and gene expression of EOCRC by racial and ethnic groups (Non-Hispanic Asian, Non-Hispanic Black, Non-Hispanic White, White Hispanic) using data from AACR Project GENIE (10.2) and University of Texas Southwestern, the latter enriched in Hispanic patients. All statistical tests were 2-sided. Of 1,752 EOCRC [...]