Menée à l'aide de données du projet "The Cancer Genome Atlas" et à l'aide d'échantillons tissulaires de carcinomes hépatocellulaires, cette étude met en évidence un mécanisme par lequel le facteur IRF-1, en réduisant l'expression de la kinase CHK1 via le microARN miR-195, augmente l'apoptose des cellules cancéreuses et l'expression de PDL-1 par ces dernières

Interferon regulatory factor 1 (IRF-1) downregulates Checkpoint kinase 1 (CHK1) through miR-195 to upregulate apoptosis and PD-L1 expression in Hepatocellular carcinoma (HCC) cells

Yan, Yihe ; Zheng, Leting ; Du, Qiang ; Cui, Xiao ; Dong, Kun ; Guo, Yarong ; Geller, David A.

Background : CHK1 is considered an oncogene with overexpression in numerous cancers. However, CHK1 signalling regulation in hepatocellular carcinoma (HCC) remains unclear. Methods : CHEK1 mRNA, protein, pri-miR-195 and miR-195 expression in HCC tissue was determined by qPCR, WB and IF staining assay. Survival analyses in HCC with high- and low-CHEK1 mRNA expression was performed using TCGA database. Relative luciferase activity was investigated in HCC cells transfected with p-CHEK1 3’UTR. [...]

Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel la protéine p53 acétylée favorise la transcription de la protéine PD-1 des cellules cancéreuses et la suppression tumorale

An unexpected role for p53 in regulating cancer cell–intrinsic PD-1 by acetylation

Cao, Zhijie ; Kon, Ning ; Liu, Yajing ; Xu, Wenbin ; Wen, Jia ; Yao, Han ; Zhang, Mi ; Wu, Zhen ; Yan, Xiaojun ; Zhu, Wei-Guo ; Gu, Wei ; Wang, Donglai

Cancer cell–intrinsic programmed cell death protein-1 (PD-1) has emerged as a tumor regulator in an immunity-independent manner, but its precise role in modulating tumor behaviors is complex, and how PD-1 is regulated in cancer cells is largely unknown. Here, we identified PD-1 as a direct target of tumor suppressor p53. Notably, p53 acetylation at K120/164 played a critical role in p53-mediated PD-1 transcription. Acetylated p53 preferentially recruited acetyltransferase cofactors onto PD-1 [...]

Menée à partir de l'analyse transcriptomique de neuroblastomes et de glandes surrénales humaines normales à divers stades du développement embryonnaire et foetal, cette étude identifie des origines du développement de la maladie

Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma

Jansky, Selina ; Sharma, Ashwini Kumar ; Körber, Verena ; Quintero, Andrés ; Toprak, Umut H. ; Wecht, Elisa M. ; Gartlgruber, Moritz ; Greco, Alessandro ; Chomsky, Elad ; Grünewald, Thomas G. P. ; Henrich, Kai-Oliver ; Tanay, Amos ; Herrmann, Carl ; Hofer, Thomas ; Westermann, Frank

Neuroblastoma is a pediatric tumor of the developing sympathetic nervous system. However, the cellular origin of neuroblastoma has yet to be defined. Here we studied the single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development. We defined normal differentiation trajectories from Schwann cell precursors over intermediate states to neuroblasts or chromaffin cells and showed that neuroblastomas transcriptionally [...]

Menée à l'aide de lignées cellulaires et de modèles murins de cancer de la peau, cette étude met en évidence le rôle de la kératine 17 dans la réponse aux dommages causés à l'ADN et dans l'initiation tumorale

A role for keratin 17 during DNA damage response and tumor initiation

Nair, Raji R. ; Hsu, Joshua ; Jacob, Justin T. ; Pineda, Christopher M. ; Hobbs, Ryan P. ; Coulombe, Pierre A.

Expression of keratin 17 (K17), an intermediate filament-forming cytoskeletal protein, is induced in a broad range of human carcinomas and has prognostic value for a growing number of tumor types. We report here that K17 is induced in response to DNA damage and that a nuclear pool of K17 regulates the immediate response to such damage, with an associated impact on cell survival. Impairing the nuclear pool of K17 markedly attenuates tumor initiation in mouse skin. Our finding adds a role for [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel l'autophagie sélective, via l'activation de la voie de signalisation cAMP/PKA par la protéine AKAP11, alimente le métabolisme mitochondrial et la croissance des cellules cancéreuses

Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth

Deng, Zhiqiang ; Li, Xianting ; Blanca Ramirez, Marian ; Purtell, Kerry ; Choi, Insup ; Lu, Jia-Hong ; Yu, Qin ; Yue, Zhenyu

Autophagy is known to promote cell survival through providing various sources of fuels as a result of digestion. Here, we uncover a function of autophagy in cell metabolic regulation by directly activating cAMP/PKA signaling that fuels mitochondrial metabolism and confers cell resistance to energy crisis. We find that autophagy selectively degrades PKA inhibitory subunit RIα through new autophagy receptor AKAP11 in response to energy crisis, thus causing PKA activation, which is a central hub [...]

Menée à l'aide de modèles murins et de données du projet "The Cancer Genome Atlas", cette étude met en évidence les rôles antagonistes des lymphocytes T CD8+ et du facteur plaquettaire CXCL4 dans l'inhibition du processus métastatique

CD8+ T cells inhibit metastasis and CXCL4 regulates its function

Joseph, Robiya ; Soundararajan, Rama ; Vasaikar, Suhas ; Yang, Fei ; Allton, Kendra L. ; Tian, Lin ; den Hollander, Petra ; Isgandarova, Sevinj ; Haemmerle, Monika ; Mino, Barbara ; Zhou, Tieling ; Shin, Crystal ; Martinez-Paniagua, Melisa ; Sahin, Aysegul A. ; Rodriguez-Canales, Jaime ; Gelovani, Juri ; Chang, Jeffrey T. ; Acharya, Ghanashyam ; Sood, Anil K. ; Wistuba, Ignacio I. ; Gibbons, Don L. ; Solis, Luisa M. ; Barton, Michelle C. ; Varadarajan, Navin ; Rosen, Jeffrey M. ; Zhang, Xiang H. ; Mani, Sendurai A.

Background : The mechanism by which immune cells regulate metastasis is unclear. Understanding the role of immune cells in metastasis will guide the development of treatments improving patient survival. Methods : We used syngeneic orthotopic mouse tumour models (wild-type, NOD/scid and Nude), employed knockout (CD8 and CD4) models and administered CXCL4. Tumours and lungs were analysed for cancer cells by bioluminescence, and circulating tumour cells were isolated from blood. [...]

Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence un mécanisme par lequel l'expression de l'intégrine alpha-v-bêta 8 sur les cellules cancéreuses favorise l'augmentation du nombre de lymphocytes T régulateurs dans le microenvironnement tumoral

A tumor-specific mechanism of Treg enrichment mediated by the integrin alpha-

Seed, Robert I. ; Kobayashi, Kenji ; Ito, Saburo ; Takasaka, Naoki ; Cormier, Anthony ; Jespersen, Jillian M. ; Publicover, Jean ; Trilok, Suprita ; Combes, Alexis J. ; Chew, Nayvin W. ; Chapman, Jocelyne ; Krummel, Matthew F. ; Lou, Jianlong ; Marks, James ; Cheng, Yifan ; Baron, Jody L. ; Nishimura, Stephen L.

Regulatory T cells (Tregs) are immunosuppressive and enriched in the tumor microenvironment (TME), which subsequently leads to the promotion of tumor growth. The mechanism behind Treg enrichment in the TME is not known. Here, Seed et al. demonstrated that integrin αvβ8 expression on tumor cells induced Treg differentiation intratumorally by binding to latent TGF-β on T cells, leading to TGF-β activation. Antibody blockade of αvβ8 depleted intratumoral Tregs and delayed tumor growth in murine [...]

Mené à l'aide de lignées cellulaires cancéreuses cultivées sur un hydrogel à double réseau simulant les tissus biologiques et menée à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence des mécanismes moléculaires par lesquels des cellules cancéreuses acquièrent les propriétés des cellules souches

Rapid reprogramming of tumour cells into cancer stem cells on double-network hydrogels

Suzuka, Jun ; Tsuda, Masumi ; Wang, Lei ; Kohsaka, Shinji ; Kishida, Karin ; Semba, Shingo ; Sugino, Hirokazu ; Aburatani, Sachiyo ; Frauenlob, Martin ; Kurokawa, Takayuki ; Kojima, Shinya ; Ueno, Toshihide ; Ohmiya, Yoshihiro ; Mano, Hiroyuki ; Yasuda, Kazunori ; Gong, Jian Ping ; Tanaka, Shinya

Cancer recurrence can arise owing to rare circulating cancer stem cells (CSCs) that are resistant to chemotherapies and radiotherapies. Here, we show that a double-network hydrogel can rapidly reprogramme differentiated cancer cells into CSCs. Spheroids expressing elevated levels of the stemness genes Sox2, Oct3/4 and Nanog formed within 24 h of seeding the gel with cells from any of six human cancer cell lines or with brain cancer cells resected from patients with glioblastoma. Human brain [...]

Menée à partir de l'analyse de profils d'expression génétique de patients atteints d'un myélome multiple et de patients atteints d'une leucémie secondaire à plasmocytes, cette étude met en évidence un mécanisme par lequel un faible niveau d'expression de l'intégrine alpha 6 favorise le processus invasif du myélome multiple ainsi que la progression de ce dernier vers une leucémie à plasmocytes

Downregulation of ITGA6 confers to the invasion of multiple myeloma and promotes progression to plasma cell leukaemia

Song, Sha ; Zhang, Ji ; Su, Qi ; Zhang, Weimin ; Jiang, Yunxin ; Fan, Gao ; Qian, Chen’ao ; Li, Bingzong ; Zhuang, Wenzhuo

Background : Secondary plasma cell leukaemia (sPCL) is an aggressive form of multiple myeloma (MM), but the mechanism underlying MM progresses into PCL remains unknown. Methods : Gene expression profiling of MM patients and PCL patients was analysed to identify the molecular differences between the two diseases. Cox survival regression and Kaplan–Meier analysis were performed to illustrate the impact of integrin subunit alpha 6 (ITGA6) on prognosis of MM. Invasion assays were performed to [...]

Menée à l'aide de modèles murins, d'échantillons tumoraux de patients atteints d'un cancer colorectal et d'échantillons de tissus coliques sains, cette étude démontre que l'altération de la barrière vasculaire intestinale entraîne la dissémination des bactéries intestinales et des cellules cancéreuses vers le foie

Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver

Bertocchi, Alice ; Carloni, Sara ; Ravenda, Paola Simona ; Bertalot, Giovanni ; Spadoni, Ilaria ; Lo Cascio, Antonino ; Gandini, Sara ; Lizier, Michela ; Braga, Daniele ; Asnicar, Francesco ; Segata, Nicola ; Klaver, Chris ; Brescia, Paola ; Rossi, Elio ; Anselmo, Achille ; Guglietta, Silvia ; Maroli, Annalisa ; Spaggiari, Paola ; Tarazona, Noelia ; Cervantes, Andres ; Marsoni, Silvia ; Lazzari, Luca ; Jodice, Maria Giovanna ; Luise, Chiara ; Erreni, Marco ; Pece, Salvatore ; Di Fiore, Pier Paolo ; Viale, Giuseppe ; Spinelli, Antonino ; Pozzi, Chiara ; Penna, Giuseppe ; Rescigno, Maria

Metastasis is facilitated by the formation of a “premetastatic niche,” which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence [...]

Menée à l'aide de lignées cellulaires de carcinome rénal à cellules claires et à l'aide de xénogreffes, cette étude met en évidence l'inutilité du métabolisme du glycogène pour la progression tumorale

Glycogen metabolism is dispensable for tumour progression in clear cell renal cell carcinoma

Xie, Hong ; Song, Jun ; Godfrey, Jason ; Riscal, Romain ; Skuli, Nicolas ; Nissim, Itzhak ; Simon, M. Celeste

Glycogen accumulation is a highly consistent, distinguishable characteristic of clear cell renal cell carcinoma (ccRCC)1. While elevated glycogen pools might be advantageous for ccRCC cells in nutrient-deprived microenvironments to sustain tumour viability, data supporting a biological role for glycogen in ccRCC are lacking. Here, we demonstrate that glycogen metabolism is not required for ccRCC proliferation in vitro nor xenograft tumour growth in vivo. Disruption of glycogen synthesis by [...]

Menée à l'aide de lignées cellulaires, de modèles murins de tumeur stromale gastro-intestinale et de pièces de résection, cette étude met en évidence un mécanisme par lequel l'inhibition de la kinase KIT atténue l'immunité antimurale induite par l'interféron de type 1

Oncogenic KIT Modulates Type I IFN–Mediated Antitumor Immunity in GIST

Liu, Mengyuan ; Etherington, Mark S. ; Hanna, Andrew ; Medina, Benjamin D. ; Vitiello, Gerardo A. ; Bowler, Timothy G. ; Param, Nesteene J. ; Levin, Lillian ; Rossi, Ferdinand ; DeMatteo, Ronald P.

Type I IFNs are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8+ T-cell [...]

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la protéine transmembranaire STING, via le recrutement de la kinase TBK1, active IRF3 et NF-kappaB, deux facteurs impliqués dans la réponse immunitaire aux infections virales et aux tumeurs

TBK1 recruitment to STING activates both IRF3 and NF-kappaB that mediate immune defense against tumors and viral infections

Yum, Seoyun ; Li, Minghao ; Fang, Yan ; Chen, Zhijian J.

The cGAS-STING pathway is important for immune defense against infection and cancer. STING activation triggers multiple signaling cascades leading to activation of IRF3, NF-κB, and autophagy. By generating mice harboring mutations of STING that specifically inactivate different signaling cascades, we found that ablation of IRF3 activation, which is essential for the induction of type I interferons, was not sufficient to abolish the immune defense against virus infection and cancer in mouse [...]