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 - 摘要转移在黑色素瘤早期开始，并与肿瘤细胞的表型和功能变化相吻合，周围的基质细胞和细胞外基质成分。在基质细胞类型中，癌症相关的成纤维细胞（CAF）正在成为特别相关的细胞群。虽然是遗传稳定，CAF在表型和功能上是多样的，发现CAF的不同子集被发现支持或抑制胰腺癌模型中的癌性生长。尽管这些发现在功能上暗示在其他癌症中也可能存在各种咖啡馆的多种咖啡馆，在大多数其他癌症类型中尚未定义它们。此外，由于特定的CAF可能是有价值的预后标记或治疗目标，因此它已成为对更好地了解其发展和监管越来越重要。在这里，我们建议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部产生异质性以及如何形成异质性在黑色素瘤细胞的一部分中释放转移性行为。为了检验这一假设，我们开发了一般设计的先天小鼠模型，使我们能够遗传操纵黑素细胞干细胞发起忠实地概括人黑色素瘤病理并独立的肿瘤抑制黑色素瘤细胞或CAF中的特定基因。这些模型将唯一使我们能够调查如何特定的信号传导机制影响CAF在黑色素瘤发育和转移中的功能。我们建议将我们的鼠标模型与单细胞RNA测序，空间转录组学，ATAC-SEQ和CHIP-SEQ相结合转录的方法定义了独特的CAF状态。我们还将与黑色素瘤一起使用来自有或没有转移性进展的患者的标本以绘制特定的CAF及其邻近性具有高度多重免疫 - 归化学的其他细胞类型（AIM 1）。接下来，我们将使用这些工具和数据来发现细胞态特异性受体 - 配体相互作用并研究黑色素瘤之间的IGF1-IGF1R信号传导细胞和CAF（一种模型途径我们的初步研究）影响肿瘤内异质性和体内转移进展（AIM 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协同作用，以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性传播。项目2还将通过抛光新光线来增强项目3 进入CAF分泌的细胞因子，该细胞因子调节肿瘤排干淋巴结并使免疫细胞耐受性转移黑色素瘤细胞。一旦我们以分子水平了解这些过程并将其链接到临床特征，我们可以开始告知患者选择以进行早期黑色素瘤的调整治疗并催化有针对性疗法的合理发展，以预防或治疗早期转移性传播阶段黑色素瘤和其他癌症类型。