Effects of extracellular vesicles on miRNA activity in the skin

细胞外囊泡对皮肤 miRNA 活性的影响

• 批准号: 10418736
• 负责人: My Georgia Mahoney
• 金额: $ 34万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418736
• 关键词: Ablation; Address; Affect; Alzheimer' s Disease; Anabolism; Biogenesis; Biological; Biological Markers; Biological Process; Blood; Cadherins; Cancer Biology; Carcinoma; Cardiomyopathies; Cell Cycle; Cell Cycle Regulation; Cell Differentiation process; Cell Polarity; Cell Proliferation; Cell surface; Cells; Clinical; Colon; Data; Defect; Development; Diagnosis; Disease; Distant; Environment; Epithelial; Etiology; Event; Experimental Models; Fibroblasts; Fibrosis; Gene Expression Profiling; Gene Silencing; Genetic; Goals; Growth and Development function; Homeostasis; Human; Hyperplasia; Incidence; Inflammation; Label; Laboratories; Light; Liquid substance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant Squamous Cell; Mediating; Membrane; Messenger RNA; MicroRNAs; Molecular; Morphogenesis; Mus; Mutation; Normal Cell; Normal tissue morphology; Oncogenic; Outcome; Paint; Pathogenicity; Pathologic; Patients; Play; Positioning Attribute; Post-Translational Protein Processing; Prognosis; Prognostic Marker; Prostate; Proteolytic Processing; Research; Respiratory System; Risk Factors; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Signaling Protein; Skin; Skin Cancer; Solid; Sorting - Cell Movement; Squamous cell carcinoma; Testing; Therapeutic; Time; Tissues; Tumor Markers; Untranslated RNA; Urinary tract infection; Vesicle; Work; base; blastomere structure; cancer cell; cell growth; cell motility; cell stroma; cell transformation; circulating biomarkers; cost; desmoglein 2; diagnostic biomarker; extracellular; extracellular vesicles; genetic signature; healthy volunteer; high risk; innovation; keratinocyte; membrane biogenesis; migration; nanosized; neoplastic cell; new therapeutic target; novel; overexpression; palmitoylation; prognostic; response; synergism; targeted treatment; therapeutic biomarker; therapeutic target; trafficking; transcriptome sequencing; translational therapeutics; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; vesicular release

PROJECT SUMMARY/ABSTRACT With more than one million new cases diagnosed yearly, skin cancer accounts for nearly half of all cancers in the U.S. Squamous cell carcinoma (SCC) is a major form of skin cancer with common genetic signatures, but without a clear mechanism of oncogenesis. Developing targeted therapies for SCCs has been challenging as the molecular etiology of the disease paints a heterogeneous picture. An emerging concept is that the synergy or crosstalk between cancer cells and the tumor microenvironment (TME) is critical for tumor initiation and progression. Essential for this cell-stroma crosstalk is the role of membrane-derived, nano-sized extracellular vesicles (EVs) secreted by tumor cells and released into the blood and other bodily fluids carrying their molecular macromolecular cargo to modulate local and distant TME. In addition to mitogenic signaling proteins and mRNAs, EVs carry miRNAs, short non-coding RNAs that repress complementary mRNAs critical for cell cycle regulation and cell proliferation and differentiation. The long-term goal of our research is to understand at the molecular and cellular level, how normal signaling events during development are subverted for pathogenic signaling during SCC progression. During malignant transformation, aberrant expression or localization of the desmosomal cadherin desmoglein 2 (Dsg2) is observed. Dsg2 plays a critical role in normal cell growth and development, which is emphasized by the fact that genetic ablation results in embryonic cell growth defects and lethality in mice. In human, mutations in Dsg2 are associated with cardiomyopathy, respiratory and urinary tract infections, and Alzheimer's disease. Overexpression of Dsg2 also occurs in various other malignancies including prostate, colon and skin, suggesting a more general role for Dsg2 in oncogenesis. The mechanism by which Dsg2 promotes cell proliferation, migration, and hyperproliferative disorders is not fully understood. The goal of this proposal is demonstrate that Dsg2 promotes oncogenesis by enhancing the release of EVs carrying cancer cell-state specific cargos capable of priming keratinocytes and fibroblasts. It is our hypothesis that cell surface presentation of Dsg2 modulates export of EV-associated miRNAs that can serve as biomarkers and key regulators of SCC cancer progression and/or invasion rendering them novel therapeutic targets. Aim 1 will determine the mechanisms by which Dsg2 modulates the biosynthesis of EVs. Aim 2 will study the cellular effects of EV-associated miR146a and miR155. Aim 3 will evaluate the utility of serum EV miRNA levels as prognostic risk factors in SCC. The results obtained here will elucidate novel functions of Dsg2 and shed new light on how Dsg2 can impact cell growth and migration: biological steps critical for proper tissue morphogenesis and tumorigenesis. Upon the successful completion of this work, we will define the mechanisms by which cellular EV export are controlled; how EVs can modulate the stromal environment; and reveal novel miRNAs that can serve as biomarkers for the diagnosis and prognosis of malignant SCCs and other epithelial-derived cancers.

项目概要/摘要 每年诊断出的新病例超过一百万，皮肤癌占所有癌症的近一半 美国鳞状细胞癌 (SCC) 是皮肤癌的一种主要形式，具有共同的遗传特征，但是 尚无明确的肿瘤发生机制。开发鳞状细胞癌的靶向疗法一直具有挑战性，因为 该疾病的分子病因学描绘了一幅异质的图景。一个新兴的概念是协同作用 或癌细胞与肿瘤微环境（TME）之间的串扰对于肿瘤的发生和发展至关重要 进展。这种细胞间质串扰的关键是膜衍生的纳米尺寸细胞外的作用 囊泡（EV）由肿瘤细胞分泌并释放到血液和其他体液中，携带其 调节局部和远端 TME 的分子大分子货物。除了促有丝分裂信号蛋白 和 mRNA，EV 携带 miRNA，即抑制对细胞至关重要的互补 mRNA 的短非编码 RNA 周期调节和细胞增殖和分化。我们研究的长期目标是了解 在分子和细胞水平上，发育过程中的正常信号事件如何被破坏 SCC 进展过程中的致病信号传导。在恶性转化期间，异常表达或 观察到桥粒钙粘蛋白桥粒糖蛋白 2 (Dsg2) 的定位。 DSg2 在正常情况下发挥着关键作用 细胞生长和发育，这一点通过遗传消除导致胚胎细胞的事实而得到强调 小鼠的生长缺陷和致死率。在人类中，Dsg2 突变与心肌病相关， 呼吸道和泌尿道感染以及阿尔茨海默病。 Dsg2 的过度表达也发生在 各种其他恶性肿瘤，包括前列腺癌、结肠癌和皮肤癌，表明 Dsg2 在 肿瘤发生。 Dsg2促进细胞增殖、迁移和过度增殖的机制 疾病尚未完全了解。该提案的目标是证明 Dsg2 促进肿瘤发生 通过增强携带能够启动角质形成细胞的癌细胞状态特异性货物的 EV 的释放 和成纤维细胞。我们的假设是 Dsg2 的细胞表面呈递调节 EV 相关的输出 可作为 SCC 癌症进展和/或侵袭的生物标志物和关键调节因子的 miRNA 使它们成为新的治疗靶点。目标 1 将确定 Dsg2 调节的机制 EV 的生物合成。目标 2 将研究 EV 相关 miR146a 和 miR155 的细胞效应。目标3将 评估血清 EV miRNA 水平作为 SCC 预后危险因素的效用。此处获得的结果将 阐明 Dsg2 的新功能，并为 Dsg2 如何影响细胞生长和迁移提供新的线索： 对于适当的组织形态发生和肿瘤发生至关重要的生物学步骤。成功完成后 这项工作，我们将定义控制蜂窝电动汽车出口的机制；电动汽车如何调节 基质环境；并揭示可作为诊断和预后生物标志物的新型 miRNA 恶性鳞状细胞癌和其他上皮源性癌症。

项目成果

Reactive oxygen species reprogram macrophages to suppress antitumor immune response through the exosomal miR-155-5p/PD-L1 pathway.

• DOI: 10.1186/s13046-022-02244-1
• 发表时间: 2022-01-27
• 期刊: Journal of experimental & clinical cancer research : CR
• 作者: Li X;Wang S;Mu W;Barry J;Han A;Carpenter RL;Jiang BH;Peiper SC;Mahoney MG;Aplin AE;Ren H;He J
• 通讯作者: He J