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.

项目摘要/摘要 每年被诊断出超过一百万个新病例，皮肤癌占所有癌症的一半 美国鳞状细胞癌（SCC）是具有常见遗传特征的皮肤癌的一种主要形式，但 没有明确的肿瘤发生机制。开发针对SCC的有针对性疗法一直具有挑战性 该疾病的分子病因描绘出异质的图片。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起始和 进展。对于这种细胞状态的串扰，必不可少的是膜衍生的纳米大小细胞外的作用 肿瘤细胞分泌的囊泡（EV），并释放到血液和其他体液中 分子大分子货物调节局部和遥远的TME。除了有丝分裂信号蛋白 和mRNA，EV携带miRNA，简短的非编码RNA，抑制对细胞至关重要的互补mRNA 循环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，开发过程中的正常信号传导如何颠覆 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 观察到脱毛蛋白脱木素2（DSG2）的定位。 DSG2在正常中起着至关重要的作用 细胞的生长和发育，这是由于遗传消融导致胚胎细胞而强调的 小鼠的生长缺陷和致死性。在人类中，DSG2中的突变与心肌病有关， 呼吸道和尿路感染以及阿尔茨海默氏病。 DSG2的过表达也发生在 包括前列腺，结肠和皮肤在内的各种其他恶性肿瘤，表明DSG2在 肿瘤发生。 DSG2促进细胞增殖，迁移和高增殖性的机制 疾病尚未完全理解。该提案的目的是证明DSG2促进了肿瘤发生 通过增强携带癌细胞态特异性陈酿的电动汽车的释放，能够启动角质形成细胞 和成纤维细胞。我们的假设是，DSG2的细胞表面表面表现调节EV相关的出口 可以用作SCC癌进展和/或入侵的生物标志物和关键调节剂的miRNA 使他们成为新颖的治疗靶标。 AIM 1将确定DSG2调节的机制 电动汽车的生物合成。 AIM 2将研究与EV相关的MIR146A和MIR155的细胞作用。目标3意志 评估血清EV miRNA水平作为SCC中预后危险因素的效用。这里获得的结果将 阐明了DSG2的新功能，并为DSG2如何影响细胞的生长和迁移提供了新的启示： 生物学步骤对于正确的组织形态发生和肿瘤发生至关重要。成功完成后 这项工作，我们将定义控制细胞EV导出的机制；电动汽车如何调制 基质环境；并揭示可作为诊断和预后的生物标志物的新型miRNA 恶性SCC和其他上皮衍生的癌症。

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