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

• 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
• 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

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.

头颈部鳞状细胞癌（HNSCC）是一种严重的恶性肿瘤