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.

项目摘要黑色素瘤仍然是一种毁灭性的癌症。早期黑色素瘤代表大多数黑色素瘤在美国被诊断和管理的。转移和播种变得越来越清楚在肿瘤进展过程中很早就发生，而肿瘤仍位于皮肤上，而没有其他迹象器官参与。要有效地与这种疾病作斗争，我们必须了解生物学早期肿瘤，特别是针对肿瘤细胞的宿主防御机制。基础研究在过去的几十年中，早期的梅洛马斯（Melomas）并没有取得重大进展，主要是由于缺乏鼠模拟早期疾病的系统。黑色素瘤的基因设计的鼠模型代表了许多缺点，充其量它们模仿小鼠免疫中的晚期侵袭性肿瘤（鼠基因组）系统。在这一建议中，我们将模仿新型的体内人性化鼠模型中的早期恶性国家，我们已经开发了高度免疫缺陷的小鼠用人CD34+造血重构干细胞并用HLA-A等位基因匹配的人黑色素瘤细胞挑战。紫外线（UVB/A）辐照，我们将像人类皮肤一样诱导其他突变，并研究肿瘤的进展在时间和空间上生长。我们的初步研究表明，转录开关发生在肿瘤细胞，它处理独特的宿主免疫反应，该串扰决定了肿瘤朝着进展或消除。干扰素的刺激器 - 刺痛 - 信号传导一次激活一次黑色素瘤细胞获得侵略性表型，表明在肿瘤进展中起作用。在这里，我们提议在非侵略性的蓝麦斯过渡到一个概念中建立范式转移积极的表型将直接影响临床实践。我们将调查：1）肿瘤内的变化（突变，途径）早期免疫微环境（细胞谱系，信号）内共发生使用人性化小鼠模型（AIM1），2）在存在下的促肿瘤反应的疾病进展或在利用人性化小鼠和3D皮肤模型的早期疾病中没有刺激激活（AIM 1）， 3）通过调节免疫细胞亚群（AIM 2）和4）的表型和测试因果关系的逆转（4）对预测生存的早期黑色素瘤的预后评估的开发和验证（AIM 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研究人类肿瘤和人类免疫系统相互作用。如果在早期提供重大飞跃黑色素瘤研究，并通过揭示新的肿瘤细胞固有或外部的新肿瘤细胞来加深我们的理解疾病进展的机制。