Dissecting Phenotype Switching in Early Stage Melanomas

剖析早期黑色素瘤的表型转换

基本信息

批准号：
10676721
负责人：
Julide T. Celebi
金额：
$ 61.29万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-04 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676721
关键词：
3-Dimensional Alleles Animals Antitumor Response Autologous B-Lymphocytes Basic Science Behavior Biological Biological Markers Biological Models Biology CD34 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell Lineage Cells Clinical Clinical Data Data Set Dermal Development Diagnosis Differentiation Antigens Disease Disease Outcome Disease Progression Epigenetic Process Etiology Exhibits Experimental Models Failure Fetal Liver Future Gene Expression Profile Genes Genetic Transcription Genetically Engineered Mouse Genome Goals Growth HLA-A gene Hematopoietic stem cells Host Defense Mechanism Human Immune Immune response Immune signaling Immune system Immunohistochemistry Immunological Models Implant In Vitro Innate Immune Response Interferons Invaded Macrophage Malignant - descriptor Malignant Neoplasms Melanoma Cell Modeling Molecular Mus Mutation Natural Killer Cells Neoplasm Metastasis Organ Pathway interactions Patients Phase Phenotype Prevention strategy Prognosis Proteins Radial Reproducibility Research Role STING agonists Signal Pathway Signal Transduction Skin Stimulator of Interferon Genes System Techniques Testing Thick Thymic Tissue Time Tissue Sample Ultraviolet B Radiation Validation Work advanced system antagonist anti-CD20 anti-tumor immune response clinical practice cohort draining lymph node genetic signature human data human model human tissue humanized mouse immune cell infiltrate immunoregulation in vivo in vivo Model innovation irradiation malignant state melanocyte melanoma mouse model neoplastic cell novel pathogen potential biomarker predictive marker prevent prognostic prognostic assays prognostication reconstitution survival prediction transcriptome tumor tumor growth tumor progression tumor-immune system interactions ultraviolet

项目摘要

Project Summary Melanoma continues to be a devastating cancer. Early stage melanomas represent the majority of melanomas that are diagnosed and managed in the US. It is becoming clearer that metastatic dissemination and seeding occurs very early during tumor progression while the tumor is still localized to the skin without signs of other organ involvement. To effectively battle with this disease we must understand the molecular underpinnings of biologically early tumors, in particular host defense mechanisms against the tumor cells. Basic research in early melanomas has not made significant progress over the past decades mostly due to lack of murine systems that model early disease. Genetically engineered murine models of melanoma represent many shortcomings, and at best they mimic late aggressive tumors (murine genome) within the mice immune system. In this proposal, we will mimic early malignant states in novel in vivo humanized murine models that we have developed, in which highly immune deficient mice are reconstituted with human CD34+ hematopoietic stem cells and challenged with HLA-A allele-matched human melanoma cells. By ultraviolet (UVB/A) irradiation, we will induce additional mutations as in human skin, and study the progression of tumors as they grow in time and space. Our preliminary studies indicate that a transcriptional switch occurs within the tumor cells, it accompanies unique host immune responses, and this crosstalk dictates the fate of the tumor towards progression or elimination. Stimulator of interferon – STING – signaling gets activated once melanoma cells acquire an aggressive phenotype suggesting a role during tumor progression. Here, we propose to establish paradigm-shifts in the concept of non-aggressive melanomas transitioning into an aggressive phenotype that will directly impact clinical practice. We will investigate: 1) changes within the tumor (mutations, pathways) that co-occur within the immune microenvironment (cell lineages, signals) during early disease progression using humanized mouse models (Aim1), 2) pro- or anti-tumor responses in the presence or absence of STING activation in early disease leveraging the humanized mouse and 3D skin models (Aim 1), 3) reversal of phenotypes and testing causality by modulating immune cell subpopulations (Aim 2), and 4) development and validation of a prognostic assay applied to early melanomas that predicts survival (Aim 3). Successful completion of this project promises to bring new model systems to the melanoma (and cancer) field that enable studying human tumor and human immune system interactions. If offers a major leap in early stage melanoma research, and deepens our understanding by revealing new tumor cell intrinsic or extrinsic mechanisms of disease progression.

项目概要黑色素瘤仍然是一种毁灭性的癌症，早期黑色素瘤占黑色素瘤的大多数。在美国诊断和管理的转移性传播和播种变得越来越清楚。发生在肿瘤进展的早期，而肿瘤仍局限于皮肤，没有其他迹象为了有效地对抗这种疾病，我们必须了解其分子基础。生物学早期肿瘤，特别是针对肿瘤细胞的宿主防御机制的基础研究。早期黑色素瘤在过去几十年中并未取得重大进展，主要是由于缺乏小鼠模拟早期疾病的系统代表了许多黑色素瘤的基因工程小鼠模型。缺点，并且充其量只能模拟小鼠免疫中的晚期侵袭性肿瘤（小鼠基因组）在这个提案中，我们将在新型体内人源化小鼠模型中模拟早期恶性状态。我们开发了一种用人类 CD34+ 造血细胞重建高度免疫缺陷的小鼠干细胞并用 HLA-A 等位基因匹配的人类黑色素瘤细胞进行紫外线 (UVB/A) 攻击。辐射，我们将像人类皮肤一样诱导额外的突变，并研究肿瘤的进展我们的初步研究表明转录转换发生在时间和空间上。肿瘤细胞，它伴随着独特的宿主免疫反应，这种串扰决定了肿瘤细胞的命运干扰素刺激器 - STING - 信号传导一旦激活黑色素瘤细胞获得侵袭性表型，表明其在肿瘤进展过程中发挥作用。提议对非侵袭性黑色素瘤转变为非侵袭性黑色素瘤的概念进行范式转变将直接影响临床实践的侵袭性表型我们将研究：1）肿瘤内的变化。（突变、途径）在早期免疫微环境（细胞谱系、信号）中同时发生使用人源化小鼠模型观察疾病进展 (Aim1), 2) 存在促肿瘤或抗肿瘤反应或利用人源化小鼠和 3D 皮肤模型在早期疾病中缺乏 STING 激活（目标 1）， 3) 通过调节免疫细胞亚群来逆转表型并测试因果关系（目标 2）和 4）开发和验证应用于早期黑色素瘤的预测生存的预后测定（目标 3）。该项目的成功完成有望为黑色素瘤（和癌症）领域带来新的模型系统这使得研究人类肿瘤和人类免疫系统的相互作用能够在早期阶段实现重大飞跃。黑色素瘤研究，通过揭示新的肿瘤细胞内在或外在来加深我们的理解疾病进展的机制。