Project 2: Contribution of the Stromal Microenvironment to Early Dissemination

项目 2：基质微环境对早期传播的贡献

基本信息

批准号：
10705081
负责人：
Mayumi Ito
金额：
$ 34.68万
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：
2022-09-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705081
关键词：
ATAC-seq Address Adjuvant Therapy Behavior Benign Cancer Control Cancerous Cell Communication Cell Lineage Cells ChIP-seq Characteristics Chromatin Clinical Clinical Data Congenic Mice Cytokine Signaling Data Dermis Development Diagnosis Disease Disseminated Malignant Neoplasm Distal Environment Epidermis Epigenetic Process Extracellular Matrix Fibroblasts Gene Cluster Genes Genetic Engineering Genetic Transcription Growth Growth Factor Heterogeneity Histones Human Human Pathology IGF1 gene IGF1R gene Immune Immune system Immunofluorescence Microscopy Immunohistochemistry Invaded Ligands Link Lymphatic Malignant Neoplasms Maps Melanoma Cell Metastatic Melanoma Metastatic Neoplasm to Lymph Nodes Modeling Molecular Mus Neoplasm Metastasis Organ Pathologic Pathway Analysis Pathway interactions Patient Selection Patients Pattern Phenotype Play Population Primary Neoplasm Process Prognostic Marker Regulation Regulator Genes Regulatory Element Research Resolution Resources Role Signal Pathway Signal Transduction Solid Neoplasm Spatial Distribution Specimen Stromal Cells Technology Testing Time Tissues Tomatoes cancer cell cancer type cell type chemokine clinically relevant cytokine differential expression draining lymph node genetic manipulation in vivo insight melanocyte melanoma metastatic process migration molecular marker morphogens mouse model neoplastic cell pancreatic cancer model prevent prognostic value programs receptor single-cell RNA sequencing stem cells synergism targeted treatment therapeutic target tool transcription factor transcriptome transcriptomics tumor tumor heterogeneity tumor initiation tumor progression tumorigenesis

项目摘要

PROJECT 2 – SUMMARY Metastasis initiates early in melanoma, and coincides with phenotypic and functional changes in tumor cells, surrounding stromal cells, and extracellular matrix components. Amongst the stromal cell types, cancer associated fibroblasts (CAFs) are emerging as a particularly relevant cell population. Although they are genetically stable, CAFs are phenotypically and functionally diverse and distinct subsets of CAFs were found to support or inhibit cancerous growth in pancreatic cancer models. Although these findings suggest functionally diverse sets of CAFs could also exist in other cancers, they have yet to be defined in most other cancer types. Furthermore, because specific CAFs might be valuable prognostic markers or therapeutic targets, it is becoming increasingly important to better understand their development and regulation. Here, we propose to investigate how signals between melanoma cells and fibroblasts create heterogeneity within tumors and how this heterogeneity unleashes metastatic behaviors in a subset of melanoma cells. To test this hypothesis, we developed genetically engineered congenic mouse models that allow us to genetically manipulate melanocyte stem cells to initiate tumors that faithfully recapitulate the pathology of human melanoma and to independently inhibit specific genes in melanoma cells or CAFs. These models will uniquely enable us to investigate how specific signaling mechanisms influence CAF functions in melanoma development and metastasis. We propose to couple our mouse models with single-cell RNA sequencing, spatial transcriptomics, ATAC-seq, and ChIP-seq approaches to transcriptionally define distinctive CAF states. We will also use them along with melanoma specimens from patients with and without metastatic progression to map specific CAFs and their proximity to other cell types with highly multiplexed immuno-histochemistry (Aim 1). Next, we will use these tools and data to discover cell state specific receptor-ligand interactions and study how IGF1-IGF1R signaling between melanoma cells and CAFs –one model pathway our preliminary studies identified – influences intratumor heterogeneity and metastatic progression in vivo (Aim 2). Project 2 will leverage the pathological, technological, and analytical resources of Cores B and C. It will synergize with Project 1 to determine whether and how melanoma cells interact with distinctive CAFs and how these interactions allow for metastatic dissemination. Project 2 will also enhance Project 3 by shedding new light onto CAF-secreted cytokines that modulate tumor draining lymph nodes and make immune cells tolerant to metastasizing melanoma cells. Once we understand these processes on a molecular level and link them to clinical characteristics, we can begin to inform patient selection for adjuvant therapy in early-stage melanoma and catalyze a rational development of targeted therapies that prevent or treat metastatic dissemination in early- stage melanoma and other cancer types.

项目 2 – 总结黑色素瘤的转移在早期就开始，并且与肿瘤细胞的表型和功能变化同时发生，周围基质细胞和细胞外基质成分在基质细胞类型中，癌症。相关成纤维细胞（CAF）正在作为一个特别相关的细胞群出现，尽管它们是。遗传稳定，CAF 在表型和功能上具有多样性，并且发现 CAF 的不同子集支持或抑制胰腺癌模型中的癌生长，尽管这些发现表明具有功能性。不同的 CAF 组也可能存在于其他癌症中，但它们尚未在大多数其他癌症类型中得到定义。此外，由于特定的 CAF 可能是有价值的预后标志物或治疗靶点，因此它正在成为更好地了解它们的发展和监管变得越来越重要。在这里，我们建议进行调查。黑色素瘤细胞和成纤维细胞之间的信号如何在肿瘤内产生异质性以及这是如何产生的异质性引发黑色素瘤细胞亚群的转移行为为了检验这一假设。开发了基因工程同源小鼠模型，使我们能够对黑素细胞进行基因操纵干细胞启动肿瘤，忠实地再现人类黑色素瘤的病理学，并独立地这些模型将使我们能够独特地研究如何抑制黑色素瘤细胞或 CAF 中的特定基因。我们提出，特定的信号机制影响黑色素瘤发展和转移中的 CAF 功能。将我们的小鼠模型与单细胞 RNA 测序、空间转录组学、ATAC-seq 和 ChIP-seq 结合起来我们还将把它们与黑色素瘤一起使用。来自有或没有转移进展的患者的样本，以绘制特定 CAF 及其与具有高度多重免疫组织化学的其他细胞类型（目标 1）接下来，我们将使用这些工具和数据。发现细胞状态特异性受体-配体相互作用并研究黑色素瘤之间的 IGF1-IGF1R 信号传导机制细胞和 CAF——我们初步研究发现的一种模型途径——影响肿瘤内异质性和体内转移进展（目标 2）。项目 2 将利用核心 B 和 C 的病理、技术和分析资源。与项目 1 协同确定黑色素瘤细胞是否以及如何与独特的 CAF 相互作用以及如何相互作用这些相互作用允许转移传播，项目 2 也将通过揭示新的线索来增强项目 3。作用于 CAF 分泌的细胞因子，调节肿瘤引流淋巴结并使免疫细胞耐受一旦我们在分子水平上了解了这些过程并将它们与转移的黑色素瘤细胞联系起来。临床特征，我们可以开始告知患者选择早期黑色素瘤的辅助治疗并促进靶向治疗的合理发展，以预防或治疗早期转移性播散分期黑色素瘤和其他癌症类型。