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The Role of the Y Chromosome in Bladder Tumor Development, Growth And Progression

Y 染色体在膀胱肿瘤发生、生长和进展中的作用

基本信息

批准号：
10629079
负责人：
DAN THEODORESCU
金额：
$ 54.31万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629079
关键词：
Address Aftercare Aggressive behavior Alanine Aminopeptidase Animal Model Antibodies Automobile Driving B-Lymphocytes Biological Bladder Bladder Neoplasm CD8-Positive T-Lymphocytes Cancer Patient Catalogs Cell Line Cell model Cells Cessation of life Chromatin Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complement Data Data Set Development Diagnosis Diagnostic Disease Exposure to Functional disorder Gene Deletion Gene Expression Profile Gene Expression Profiling Gene Structure Genes Growth Immune Immune Evasion Immune response Immune system Immunity Immunocompetent Immunophenotyping Incidence Knockout Mice Knowledge Libraries Macrophage Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Molecular Mus Mutagenesis Myelogenous Myeloid Cells Natural Killer Cells Neoplasm Metastasis Nitrosamines Normal Cell Operative Surgical Procedures Outcome Patient-Focused Outcomes Patients Phenotype Precision therapeutics Process Prognosis Proteins Proteomics Risk Role Smoking T-Lymphocyte Technology Testing The Cancer Genome Atlas Therapeutic Therapeutic Intervention Tobacco Translating Tumor-associated macrophages Urothelial Cell Urothelium Wild Type Mouse Woman X Chromosome Y Chromosome anti-PD-1 anti-PD1 therapy autosome cancer cell cancer risk cancer type chemical carcinogen chromosome Y loss combinatorial differential expression druggable target effective intervention exhaust functional genomics genetic signature histone demethylase immune cell infiltrate immune checkpoint blockade in vivo inhibitor intravesical loss of function male men mortality risk mosaic analysis mutant neoplastic cell next generation sequencing novel overexpression paralogous gene patient prognosis patient stratification pharmacologic prognostic prognostic indicator programmed cell death protein 1 recombinase sex transcriptome sequencing treatment response tumor tumor growth tumor progression tumor-immune system interactions tumorigenesis

项目摘要

PROJECT 2 – SUMMARY Loss of the Y chromosome (LOY) is associated with increased risk of cancer development and death in men with several cancer types. In bladder cancer (BC), a tobacco related malignancy, LOY is seen in ~30% of tumors, yet the biological relevance of this is unknown. Here we address this Knowledge Gap with the Objective to define the molecular mechanisms responsible for LOY driven growth and progression and have Impact by translating these into effective interventions for bladder and other cancer types. Preliminary Data: We examined TCGA BC RNAseq dataset using an LOY gene signature we developed, and found low signature scores associated with reduced patient survival following surgery. To determine if LOY drives BC growth, we developed lineage related male murine cell lines with (Y+) or w/o (Y-) Y chromosome. Y- tumors grew faster than Y+ tumors in immunocompetent mice and cytometric profiling found the former to have increased immunosuppressive tumor-associated macrophages, CD8+ T cells with exhausted phenotype while latter had increased NK cells. In mice (Rag2-/-;Il2rg-/-) that are devoid of T, B and NK cells, Y+ and Y- tumors grew similarly. Transcriptional profiling found four Y chromosome genes differentially expressed in these tumor types, with chromatin organization genes Uty and Kdm5d being the only ones whose expression stratified outcome in TCGA BC patients. Thus, we genetically deleted these genes in Y+ cells and found enhanced tumor growth only in immunocompetent mice while their overexpression in Y- cells reduced their growth. Hence, we test the Hypothesis that Uty and Kdm5d loss enhance BC growth and progression via creation of an immunosuppressive tumor microenvironment in three Specific Aims. In Aim 1 we determine role of Uty and Kdm5d in tumor development and progression using full and urothelial specific conditional Kdm5d or Uty null mice be exposed to the chemical carcinogen BBN. With Project 3 we test the hypothesis that Uty and its X chromosome paralog Utx (aka, Kdm6a) have independent suppressive effects on BC formation and progression by crossing full and urothelial specific conditional Uty and Utx null mice and exposing them to BBN. In Aim 2 we define how Kdm5d and Uty suppress BC and the role of the immune system in this process using defined LOF functional mutants to define the regions on these proteins responsible for tumor growth suppression. With Project 1, we use spatial proteomics to examine immunological infiltrates in relation to mutant and WT Kdm5d and Uty cancer cell expression and various knockout mice or antibody depletion strategy to define which cellular components of the immune system drive tumor growth differences. In Aim 3 we examine ANPEP, the most upregulated gene in Y- tumors that is also a poor prognostic in BC patients and druggable target, as a candidate autosomal effector gene driving Y- tumor growth. We found Y- tumors are more responsive than Y+ tumors to anti-PD-1 and ANPEP depletion in Y- cells made tumors more sensitive to anti-PD-1. Here we will examine the impact of ANPEP deletion or pharmacologic inhibition on the efficacy of anti-PD-1 immune checkpoint blockade therapy.

项目2 -总结