权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Project 2: Investigating cell intrinsic and extrinsic drivers of prostate cancer bone metastasis

项目2：研究前列腺癌骨转移的细胞内在和外在驱动因素

基本信息

批准号：
10612353
负责人：
Cory Abate-Shen
金额：
$ 47.35万
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/10612353
关键词：
3-Dimensional Address Affect Allografting Androgens Biological Biological Assay Bromodomain CRISPR screen Cancer Etiology Cells Cellular Structures Cessation of life Coculture Techniques Collaborations Complement Data EP300 gene Early Diagnosis Evolution Foundations Genetic Complementation Test Genetically Engineered Mouse Habitats Human Immune Immunologic Deficiency Syndromes In Vitro Investigation LoxP-flanked allele Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Molecular Morbidity - disease rate Mus Neoplasm Metastasis Pathway interactions Patient-Focused Outcomes Population Primary Neoplasm Process Proteins Regulation Research Role Signal Transduction Site Specific qualifier value Specificity Tropism Tumor-associated macrophages Validation Xenograft Model Xenograft procedure bone candidate identification candidate validation cofactor data management deprivation genome-wide improved outcome in vivo in vivo Model insight member men mortality mouse model neoplastic cell neuroendocrine differentiation novel organ on a chip prostate cancer metastasis prostate carcinogenesis single cell sequencing transcription factor tumor microenvironment tumor progression

项目摘要

Project Summary/Abstract The objective of our research is to elucidate tumor cell intrinsic and extrinsic mechanisms that give rise to bone metastasis and specify bone tropism. The foundation for our studies is the NPKYPF mouse model, which develops highly penetrant bone metastasis that is well-conserved with bone metastasis in human prostate cancer. Analyses of these mice enable investigations of the evolution of bone metastases during cancer progression in the native microenvironment in androgen-intact and androgen-deprived contexts. We have found that co-activation of MYC and RAS signaling is essential for bone metastasis, and that MYC activation is particularly relevant in contexts of androgen deprivation. Our preliminary studies have identified ATAD2 as a MYC-co-factor that is expressed in bone metastasis, particularly in contexts of androgen deprivation, and necessary for bone metastasis. In a complementary genome-wide in vivo CRISPR screening based on human prostate cancer xenografts, we identified CITED2, another MYC co-factor, as a cell-intrinsic driver of bone metastasis that it is sufficient to promote bone metastasis in vivo. Furthermore, single cell sequencing of primary tumors and bone metastases from NPKYPF mice has led to the identification master regulators (MRs) that are candidate cell intrinsic drivers of bone metastasis, while analyses of the non-tumor components have shown that primary tumors from metastatic NPKYPF mice are deficient for most immune cell populations, but highly enriched for tumor associated macrophages. Thus, we will investigate the hypothesis that bone metastasis represents the culmination of cell intrinsic drivers from the metastatic cells and tumor cell extrinsic factors in microenvironment of the metastatic bone. In Aim 1, we will investigate the hypothesis that CITED2 collaborates with MYC to promote bone specificity. In parallel, we will investigate candidate master regulators (MRs) associated with RAS pathway activation to elucidate their potential roles in bone metastasis. In Aim 2, we will investigate the hypothesis that ATAD2 is a co-factor for MYC in contexts of androgen deprivation, and elucidate the relationship of androgen status for the evolution and underlying mechanisms of bone metastasis. In Aim 3, we will investigate cell extrinsic mechanisms in the microenvironment of the primary tumor and metastatic bone, to identify relevant cell populations associated with metastasis, to evaluate their functional role for bone metastasis, and to identify cell extrinsic drivers of bone metastasis. Integration: Our studies are highly complementary to investigations of the tumor microenvironment for neuroendocrine differentiation (Project 3) and tumor progression (Project 1). Validation of candidate regulators for human bone metastasis will require Core A. Further, our systematic analysis of bone metastasis at the single cell level, complement efforts in Projects 1 and 3, while our ability to mutually benefit from these data will be enabled by the data management component of Core B.

项目总结/文摘