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Project 1: Investigation of immune and stromal factors that promote prostate adenocarcinoma progression and castration response

项目1：促进前列腺腺癌进展和去势反应的免疫和基质因子的研究

基本信息

批准号：
10333943
负责人：
CHARLES L. SAWYERS
金额：
$ 69.5万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10333943
关键词：
Abate Address Affect Alleles Androgen Antagonists Androgen Receptor Antiandrogen Therapy Antibodies Area Biological Assay Biology Blocking Antibodies Bone Marrow CSF1R gene Castration Cells Clinic Clinical Clinical Research Collaborations Combined Modality Therapy Data Data Set Disease Disease Progression Drug Targeting Ensure Epithelial Epithelial Cells Epithelial-Stromal Communication FDA approved Fibroblasts Fluorescence Gene Expression Profile Gene Expression Profiling Genetically Engineered Mouse Genomic approach Genomics Hormonal Hormone use Human Immune Immune checkpoint inhibitor Infiltration Inflammatory Investigation Laboratory Finding Large-Scale Sequencing Lead Localized Disease Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Mesenchymal Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Neurosecretory Systems Organoids Outcome Pathogenesis Pathway interactions Play Population Prostate Prostate Adenocarcinoma Prostatic Neoplasms Proteins Publishing Receptor Inhibition Receptor Signaling Reporter Role Sampling Signal Transduction Sorting - Cell Movement Stromal Cells T-Lymphocyte Technology Tissue Recombination Tissue Sample Translating Tumor Cell Invasion Tumor-infiltrating immune cells Uncertainty WNT Signaling Pathway Work advanced disease advanced prostate cancer antagonist base cytokine data management drug efficacy experience hormone therapy human tissue improved in vivo insight neoplastic cell neuroendocrine differentiation novel programs prostate cancer model prostate cancer progression recombinase reconstitution resistance mechanism response single cell sequencing single cell technology single-cell RNA sequencing tissue resource tool treatment effect treatment response tumor tumor growth tumor microenvironment tumor progression

项目摘要

Project Summary/Abstract Large scale sequencing efforts have comprehensively defined the genomic landscape of localized and metastatic prostate cancer, yielding an improved understanding of drivers of disease initiation and progression and greater insight into mechanisms of resistance to androgen receptor (AR) pathway inhibition. One limitation of this “tumor cell focused” genomic approach is a relative lack of insight into how the tumor microenvironment (TME) plays a role. However, recent advances in single cell sequencing technologies have opened the door to comprehensively examine tumor/microenvironment interactions with unprecedented precision. Our group has embraced this approach: initially to characterize epithelial/stromal interactions in the normal prostate, and now to delineate tumor cell/microenvironment interactions in genetically engineered mouse models (GEMMs) of prostate cancer. These studies reveal a striking level of complexity. We have not only defined previously unknown subpopulations of luminal epithelial and stromal cells in the normal prostate gland, but also we have shown how these populations change/evolve during progression to invasive disease and in response to AR pathway inhibition (i.e. castration). In addition, our preliminary data showing that depletion of tumor-infiltrating immune cells delays disease progression eliminates any doubt that these TME changes are secondary phenomena. Based on these findings, we hypothesize that the prostate TME (immune cells and stromal cells) plays a crucial role in disease progression. We will explore this hypothesis through three synergistic specific aims that: (i) address the mechanism by which tumor infiltrating immune cells enhance tumor progression; (ii) elucidate how changes in Wnt pathway signaling in prostate stroma promote invasion by tumor epithelium; and (iii) determine whether/how the response of prostate tumors to AR pathway inhibition is influenced by inhibition of AR in the surrounding TME cells. We have extensive experience with the GEMMs, tissue recombination assays and organoid culture that will be used to address these questions. We also have a strong track record of translating laboratory findings to the clinic, which will ensure the human relevance of our findings. Finally, this project is highly integrated with all other components of this program project: through collaborative interactions with the Shen lab in analyzing the transition to neuroendocrine disease, with the Abate-Shen lab in studies of Wnt pathway signaling in bone metastasis, with Core A for analysis of human tissue samples and with Core B for statistical support and data management.

项目总结/文摘