Defining the β-catenin/CBP-catenin/CBP axis in head and neck cancer

定义头颈癌中的 β-连环蛋白/CBP-连环蛋白/CBP 轴

基本信息

批准号：
10312814
负责人：
MARIA A. KUKURUZINSKA
金额：
$ 63.92万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-07 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10312814
关键词：
Acetylation Adhesions Alcohols Automobile Driving Benign Binding Binding Proteins Biochemical Biological Markers Biology CREBBP gene Cancerous Carcinoma Cell Line Cell Proliferation Cells Cetuximab Chromatin Structure Complex Computing Methodologies Coupled Cyclic AMP Cyclic AMP Response Element DNA Sequence Alteration Data Development Diagnosis Disease E-Cadherin Elements Embryo Epidermal Growth Factor Receptor Epigenetic Process Event FDA approved Gene Expression Gene Expression Profile Generations Genomics Goals HPV-negative head and neck cancer Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Human Papillomavirus Immunotherapy Knowledge Lesion MLL gene Malignant Neoplasms Maps Mediating Mesenchymal Metastatic Neoplasm to Lymph Nodes Metastatic to Molecular Monoclonal Antibodies Morbidity - disease rate Mouth Diseases Neoplasm Metastasis Nuclear Nude Mice Oncogenic Oral Characters Outcome Pathway interactions Patient-Focused Outcomes Patients Pharmacology Phenotype Prognostic Marker Progressive Disease Protein Inhibition Proteins Publishing Resistance Role Signal Pathway Signal Transduction Signaling Protein Survival Rate Testing The Cancer Genome Atlas Tobacco Transcription Initiation Site Tumor stage Tumor-Derived Work Zebrafish advanced disease antagonist anti-PD-1 base beta catenin cancer stem cell carcinogenesis chemotherapy chromatin immunoprecipitation combat draining lymph node epigenomics genetic signature head and neck cancer patient histone acetyltransferase histone methyltransferase improved insight malignant mouth neoplasm mortality mouse model mouth squamous cell carcinoma oral lesion prognostic value protein complex recruit response restoration single-cell RNA sequencing small molecule small molecule inhibitor stem cell genes stem-like cell targeted treatment therapy resistant trait transcriptome sequencing treatment response treatment strategy tumor tumor growth tumor progression tumor xenograft

项目摘要

Head and neck squamous cell carcinoma (HNSCC) is a devastating malignancy associated with severe morbidity, high mortality and limited treatment options. The main subsite of HNSCC is the oral cavity, where the disease presents primarily as tobacco- and alcohol-associated HPV(-) oral squamous cell carcinoma (OSCC). Despite great progress in the understanding of genomic alterations in OSCC, the molecular details underlying the progression of non-invasive oral lesions to advanced disease with lymph node metastasis remain poorly understood. To gain insights into the mechanisms that contribute to OSCC progression to metastasis we have studied the interaction between nuclear β-catenin and cAMP-response element-binding (CREB)-binding protein (CBP) in OSCC by applying our newly developed computational methodologies coupled with genomic, epigenetic, molecular, biochemical and functional analyses. Our published and preliminary studies show that inhibition of β-catenin/CBP activity with small molecule antagonists, ICG-001 and E7386, in a panel of OSCC cell lines inhibits cell proliferation and mesenchymal phenotype while inducing cellular differentiation. Similarly, inhibition of β-catenin/CBP signaling in human OSCC cell line-derived tumor xenografts in nude mice inhibits tumor growth and metastasis and abrogates rapid metastases driven by subpopulations of OSCC stem cell-like cells, or cancer stem cells (CSCs), in embryonic zebrafish. Our recent global chromatin immunoprecipitation followed by sequencing (ChIPseq) studies show that β-catenin/CBP collaborates with the histone methyltransferase, MLL1, to promote global H3K4 trimethylation (H3K4me3) at transcription start sites (TSS) of numerous CSC genes. This finding is supported by our recent genomic analyses based on RNAseq and scRNAseq data showing that β-catenin/CBP activity is associated with aggressive cell states, including CSCs. Preliminary analyses also suggest that β-catenin/CBP complexes include the Hippo pathway effectors YAP and TAZ (YAP/TAZ), which, like β-catenin, are associated with resistance to both chemotherapy and cetuximab in HNSCC (19,20). Using well characterized OSCC cell lines, we integrated gene expression signatures associated with the inhibition of the β-catenin/CBP axis with OSCC data from The Cancer Genome Atlas (TCGA) to show that β-catenin/CBP activity is associated with progressive disease and reduced patient survival. Building on these collective findings we hypothesize that aberrant activation of β-catenin/CBP signaling underlies the expansion CSCs during HNSCC progression to metastatic disease and that its antagonism may inhibit advanced disease. This hypothesis will be tested in two aims that will: 1) define the role of the β-catenin/CBP axis in HNSCC progression to advanced disease; and 2) determine the molecular mechanisms underlying β-catenin/CBP activity in the induction of CSC phenotypes. Our studies will generate a dynamic integrated map aligning β-catenin-CBP- activity with distinct aggressive cell states and their associated in gene signatures, signaling networks and protein assemblies and provide a rationale for the development of new treatment strategies to combat this malignancy.

头颈鳞状细胞癌 (HNSCC) 是一种破坏性恶性肿瘤，与严重的癌症相关发病率高、死亡率高且治疗选择有限。 HNSCC 的主要部位是口腔。该疾病主要表现为与烟草和酒精相关的 HPV(-) 口腔鳞状细胞癌 (OSCC)。尽管对 OSCC 基因组改变的理解取得了很大进展，但其背后的分子细节非侵入性口腔病变进展至伴有淋巴结转移的晚期疾病的进展仍然缓慢为了深入了解导致 OSCC 进展为转移的机制，我们进行了研究。研究了核 β-连环蛋白和 cAMP 反应元件结合 (CREB) 结合蛋白之间的相互作用 (CBP) 通过应用我们新开发的计算方法与基因组相结合，在 OSCC 中我们发表的表观遗传学、分子、生化和功能分析表明。在一组 OSCC 中使用小分子拮抗剂 ICG-001 和 E7386 抑制 β-catenin/CBP 活性细胞系抑制细胞增殖和间充质表型，同时诱导细胞分化。抑制裸鼠人 OSCC 细胞系来源的肿瘤异种移植物中的 β-catenin/CBP 信号传导抑制肿瘤生长和转移并消除由 OSCC 干细胞样亚群驱动的快速转移我们最近对胚胎斑马鱼中的细胞或癌症干细胞（CSC）进行了整体染色质免疫沉淀。随后的测序 (ChIPseq) 研究表明 β-catenin/CBP 与组蛋白协同作用甲基转移酶 MLL1 促进转录起始位点 (TSS) 处的整体 H3K4 三甲基化 (H3K4me3) 我们最近基于 RNAseq 的基因组分析支持了这一发现。 scRNAseq 数据显示 β-catenin/CBP 活性与侵袭性细胞状态（包括 CSC）相关。初步分析还表明，β-连环蛋白/CBP 复合物包括 Hippo 通路效应子 YAP 和 TAZ (YAP/TAZ)，与 β-连环蛋白一样，与化疗和西妥昔单抗的耐药性相关 HNSCC (19,20) 使用特征明确的 OSCC 细胞系，我们整合了相关的基因表达特征。通过癌症基因组图谱 (TCGA) 的 OSCC 数据显示 β-连环蛋白/CBP 轴的抑制 β-连环蛋白/CBP 活性与疾病进展和患者生存率降低有关。我们的集体发现探索了 β-连环蛋白/CBP 信号传导的异常激活是扩张的基础 HNSCC 进展为转移性疾病期间的 CSC，其拮抗作用可能会抑制晚期疾病。该假设将通过两个目标进行检验：1) 定义 β-连环蛋白/CBP 轴在 HNSCC 中的作用进展为晚期疾病；2) 确定 β-连环蛋白/CBP 活性的分子机制我们的研究将生成一个比对 β-catenin-CBP- 的动态整合图谱。具有不同侵袭性细胞状态的活性及其与基因特征、信号网络和蛋白质的相关性集会并为制定新的治疗策略来对抗这种恶性肿瘤提供了理由。