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mRNA delivery in cancer immunotherapy

Acta Pharmaceutica Sinica B 2023年第4期13卷 1348-1357页

作者： Yichen Zhong Shi Du Yizhou Dong Division of Pharmaceutics&Pharmacology College of PharmacyThe Ohio State UniversityColumbusOH 43210USA Department of Radiation oncology Department of Biomedical EngineeringCenter for Clinical and Translational ScienceComprehensive Cancer CenterDorothy M.Davis Heart&Lung Research InstituteCenter for Cancer EngineeringCenter for Cancer MetabolismPelotonia Institute for Immune-OncologyThe Ohio State UniversityColumbusOH 43210USA Icahn Genomics institute Precision Immunology InstituteDepartment of Oncological SciencesTisch Cancer InstituteFriedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkNY 10029USA

Messenger RNA(mRNA)has drawn much attention in the medical *** various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for ***,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular ***,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA *** this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer *** also highlight promising treatment regimens and their clinical translation.

关键词： Cancer immunotherapy Lipid nanoparticles Lipid—polymer hybrid nanoparticles Messenger RNA mRNA delivery Polymeric nanoparticles Protein/peptide-mediated nanoparticles

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Pancreatic cancer cells render tumor-associated macrophages metabolically reprogrammed by a GARP and DNA methylation-mediated mechanism

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Signal Transduction and Targeted Therapy 2021年第11期6卷 3348-3365页

作者： Mengwen Zhang Xingyi Pan Kenji Fujiwara Noelle Jurcak Stephen Muth Jiaojiao Zhou Qian Xiao Anqi Li Xu Che Zihai Li Lei Zheng Department of oncology Johns Hopkins University School of MedicineBaltimoreMD21287USA The Sidney Kimmel Cancer Center Johns Hopkins University School of MedicineBaltimoreMD21287USA The Pancreatic Cancer Precision Medicine Center of Excellence Program Johns Hopkins University School of MedicineBaltimoreMD21287USA The Cellular and Molecular Medicine Graduate Program Johns Hopkins University School of MedicineBaltimoreMD21287USA pelotonia institute for immune-oncology The Ohio State University Comprehensive Cancer CenterColumbusOH43210USA Department of Surgery Johns Hopkins University School of MedicineBaltimoreMD21287USA The Second Affiliated Hospital Zhejiang University School of MedicineHangzhouChina Department of Surgery Sada HospitalFukuokaJapan Cancer Hospital Chinese Academy of Medical SciencesShenzhenChina

How tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We thus conducted a study by employing a PDA-macrophage co-culture system, an “orthotopic” PDA syngeneic mouse model, and human PDA specimens, together with macrophages derived from GARP knockout mice and multiple analytic tools including whole-genome RNA sequencing, DNA methylation arrays, multiplex immunohistochemistry, metabolism measurement, and invasion/metastasis assessment. Our study showed that PDA tumor cells, through direct cell–cell contact, induce DNA methylation and downregulation of a panel of glucose metabolism and OXPHOS genes selectively in M1-like macrophages, leading to a suppressed glucose metabolic status in M1-like but not in M2-like macrophages. Following the interaction with PDA tumor cells, M1-like macrophages are reprogrammed phenotypically to M2-like macrophages. The interaction between M1-like macrophages and PDA cells is mediated by GARP and integrin αV/β8, respectively. Blocking either GARP or integrin would suppress tumor-induced DNA methylation in Nqo-1 gene and the reprogramming of M1-like macrophages. Glucose-response genes such as Il-10 are subsequently activated in tumor-educated M1-like macrophages. Partly through Il-10 and its receptor Il-10R on tumor cells, M1-like macrophages functionally acquire a pro-cancerous capability. Both exogenous M1-like and M2-like macrophages promote metastasis in a mouse model of PDA while such a role of M1-like macrophages is dependent on DNA methylation. Our results suggest that PDA cells are able to reprogram M1-like macrophages metabolically and functionally through a GARP-dependent and DNA methylation-mediated mechanism to adopt a pro-cancerous fate.

关键词： metabolism metastasis mediated

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McSNAC:A software to approximate first-order signaling networks from mass cytometry data

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Quantitative Biology 2023年第1期11卷 59-71页

作者： Darren Wethington Sayak Mukherjee Jayajit Das Steve and Cindy Rasmussen institute for Genomic Medicine Abigail Wexner Research InstituteNationwide Children’s HospitalColumbusOhio 43205United States Biomedical Sciences Graduate Program College of MedicineThe Ohio State UniversityColumbusOhio 43210United States Department of Pediatrics College of MedicineThe Ohio State UniversityColumbusOhio 43210United States pelotonia institute for Immuno-oncology College of MedicineThe Ohio State UniversityColumbusOhio 43210United States DepartmentofBiomedicalInformatics CollegeofMedicineTheOhioStateUniversityColumbusOhio43210United States Biophysics Graduate Program The Ohio State UniversityColumbusOhio 43210United States Battelle Memorial institute ColumbusOhio 43201United States

Background:Mass cytometry(CyTOF)gives unprecedented opportunity to simultaneously measure up to 40 proteins in single cells,with a theoretical potential to reach 100 *** high-dimensional single-cell information can be very useful in dissecting mechanisms of cellular *** particular,measuring abundances of signaling proteins like phospho-proteins can provide detailed information on the dynamics of single-cell signaling ***,computational analysis is required to reconstruct such networks with a mechanistic ***:We propose our Mass cytometry Signaling Network Analysis Code(McSNAC),a new software capable of reconstructing signaling networks and estimating their kinetic parameters from CyTOF *** approximates signaling networks as a network of first-order reactions between *** assumption often breaks down as signaling reactions can involve binding and unbinding,enzymatic reactions,and other nonlinear ***,McSNAC may be limited to approximating indirect interactions between protein species,as cytometry experiments are only able to assay a small fraction of protein species involved in ***:We carry out a series of in silico experiments here to show(1)McSNAC is capable of accurately estimating the ground-truth model in a scalable manner when given data originating from a first-order system;(2)McSNAC is capable of qualitatively predicting outcomes to perturbations of species abundances in simple second-order reaction models and in a complex in silico nonlinear signaling network in which some proteins are ***:These findings demonstrate that McSNAC can be a valuable screening tool for generating models of signaling networks from time-stamped CyTOF data.

关键词： single-cell CyTOF data signaling network kinetics ODE McSNAC

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Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma

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Journal of Molecular Cell Biology 2023年第5期15卷 66-79页

作者： Liyuan Qian Zhentao Liang Zihao Wang Jiuru Wang Xin Li Jingmin Zhao Zihai Li Lizhao Chen Yongai Liu Ying Ju Changfei Li Songdong Meng Key Laboratory of Pathogen Microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeĳing 100101China University of Chinese Academy of Science Beĳing 100049China Department of Pathology and Hepatology The Fifth Medical CentreChinese PLA General HospitalBeĳing 100039China pelotonia institute for Immuno-oncology The Ohio State University Comprehensive Cancer Center—The JamesColumbusOH 43210USA

Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and *** findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.

关键词： gp96 AFP NR5A2 RanBP2 SUMOylation

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Lipid metabolism reprogramming and its potential targets in cancer

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Cancer Communications 2018年第1期38卷 291-304页

作者： Chunming Cheng Feng Geng Xiang Cheng Deliang Guo Department of Radiation oncology The Ohio State University James Comprehensive Cancer Center and College of MedicineColumbusOH 43210USA

Reprogramming of lipid metabolism is a newly recognized hallmark of *** lipid uptake,storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor *** constitute the basic struc-ture of membranes and also function as signaling molecules and energy *** regulatory element-binding proteins(SREBPs),a family of membrane-bound transcription factors in the endoplasmic reticulum,play a central role in the regulation of lipid *** studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor *** cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor,thus linking glucose metabolism and de novo lipid *** altered lipid metabolic pathways has become a promising anti-cancer *** review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy,and highlights potential molecu-lar targets and their inhibitors for cancer treatment.

关键词： Lipid metabolism Cancer SCAP SREBPs Fatty acids Cholesterol Lipid droplets

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脂质代谢重编程及其在癌症中潜在靶点的研究

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癌症 2018年第11期37卷 473-493页

作者： Chunming Cheng Feng Geng Xiang Cheng Deliang Guo Department of Radiation oncology The Ohio State University James Comprehensive Cancer Center and College of Medicine

脂质代谢的重编程是恶性肿瘤的一个新特征。在多种癌症中,脂肪摄取、储存和脂肪生成均被上调,这也促进了肿瘤的快速生长。脂质是构成膜的基本结构,并且具有信号分子和能量来源的功能。固醇调节元件结合蛋白(Sterol regulatory element-b... 详细信息

脂质代谢的重编程是恶性肿瘤的一个新特征。在多种癌症中,脂肪摄取、储存和脂肪生成均被上调,这也促进了肿瘤的快速生长。脂质是构成膜的基本结构,并且具有信号分子和能量来源的功能。固醇调节元件结合蛋白(Sterol regulatory element-binding proteins,SREBPs)是内质网中一类膜结合转录因子,在调节脂质代谢中起着核心作用。最近的研究表明,SREBPs在各种癌症中高度上调并促进肿瘤生长。SREBP切割激活蛋白(SREBP cleavage-activating protein,SCAP)是SREBPs转运和激活的关键转运蛋白,也是一种关键的葡萄糖传感器,因此它将葡萄糖代谢与脂类从头合成联系在一起。靶向变异的脂质代谢途径已成为一种很有前景的抗癌策略。本综述总结了近年来我们所知的对恶性肿瘤中脂质代谢调节的最新研究进展,并着重介绍了癌症治疗中潜在的分子靶点及其抑制剂。

关键词：脂质代谢癌症 SCAP SREBPs 脂肪酸胆固醇脂滴

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