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Principal Investigator: MARIA A. KUKURUZINSKA
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $633,640
Funding agency: National Institute of Dental and Craniofacial Research
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.
Terms: <3'5'-cyclic ester of AMP><ALL1><ALL1 gene><Acetylation><Acute Lymphoblastic Leukemia Protein 1><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adhesions><Alcohol Chemical Class><Alcohols><Anti-EGFR Monoclonal Antibody><Anti-Epidermal Growth Factor Receptor Monoclonal Antibody><Athymic Mice><Athymic Nude Mouse><Automobile Driving><Benign><Beta Cadherin-Associated Protein><Beta-1 Catenin><Binding><Binding Proteins><Biochemical><Biological Markers><Biology><Brachydanio rerio><Buccal Cavity><Buccal Cavity Head and Neck><CUL-2><CXXC7><Cadherin-1><Cancer Induction><Cancerous><Cancers><Carcinoma><Cavitas Oris><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Line><Cell Signaling><CellLine><Cells><Cetuximab><ChIP assay><Chromatin Structure><Clinical Treatment Moab><Collaborations><Complex><Computing Methodologies><Coupled><Cyclic AMP><Cyclic AMP Response Element><DNA Alteration><DNA Sequence Alteration><DNA mutation><Danio rerio><Data><Development><Diagnosis><Disease><Disorder><Drosophila Homolog of Trithorax><E-Cadherin><EGF Receptor><EGFR><ERBB Protein><Elements><Embryo><Embryonic><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Calcium-Dependent Adhesion Protein><Epithelial cancer><Epithelial-Cadherin><Event><Expression Signature><FDA approved><Gene Expression><Gene Expression Profile><Generations><Genetic mutation><Genomics><Goals><HER1><HNC patient><HNSCC><HPV [-]><HPV negative><HPV(-)><HPV(-) HNSCC><HPV(-) head and neck squamous cell carcinoma><HPV- HNSCC><HPV-negative HNSCC><HPV-negative head and neck cancer><HPV-negative head and neck squamous cell carcinoma><HRX><Head and Neck Cancer><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Histone Acetylase><Human><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Inhibition of Cell Proliferation><Intracellular Communication and Signaling><KMT2A><Knowledge><Lesion><Ligand Binding Protein><Ligand Binding Protein Gene><Lysine-Specific Methyltransferase 2A><MLL gene><MLL1><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Head and Neck Neoplasm><Malignant Neoplasms><Malignant Oral Cavity Neoplasm><Malignant Oral Cavity Tumor><Malignant Oral Neoplasm><Malignant Tumor><Maps><Mediating><Mesenchymal><Metastasis><Metastasis to Lymph Nodes><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to Lymph Nodes><Metastatic Tumor><Metastatic Tumor to Lymph Nodes><Methylation><Mixed Lineage Leukemia Gene><Mixed-Lineage Leukemia Protein><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Mouth><Mouth Cancer><Multiple lineage leukemia 1><Myeloid-Lymphoid Leukemia Gene><Myeloid-Lymphoid Leukemia Protein><Myeloid/Lymphoid Leukemia Gene><Myeloid/Lymphoid Or Mixed Lineage Leukemia Protein><Myeloid/Lymphoid or Mixed Lineage Leukemia Gene><Negative Control of Cell Proliferation><Negative Regulation of Cell Proliferation><Neoplasm Metastasis><Nuclear><Nude Mice><Oncogenic><Oral Cancer><Oral Cavity Squamous Cell Carcinoma><Oral Characters><Oral cavity><Oral squamous cell carcinoma><Outcome><PRO2286><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phenotype><Prognostic Marker><Progressive Disease><Protein Binding><Proteins><Proto Oncogene Proteins MLL><Publishing><RNA Seq><RNA sequencing><RNAseq><Resistance><Role><SCCHN><Secondary Neoplasm><Secondary Tumor><Sequence Alteration><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stem Cell like><Strains Cell Lines><Survival Rate><T-Stage><TCGA><TGF-alpha Receptor><Testing><The Cancer Genome Atlas><Tobacco><Transcription Initiation Site><Transcription Start Site><Transforming Growth Factor alpha Receptor><Tumor stage><Urogastrone Receptor><Uvomorulin><Work><Zebra Danio><Zebra Fish><Zebrafish><Zinc Finger Protein HRX><aPD-1><aPD1><absence of HPV><absence of human papillomavirus><adenosine 3'5' monophosphate><advanced disease><advanced illness><antagonism><antagonist><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-programmed cell death protein 1><antiPD-1><antiPD1><beta catenin><bio-markers><biologic marker><biological signal transduction><biomarker><bound protein><c-erbB-1><c-erbB-1 Protein><cAMP><cAMP Response Element><cancer metastasis><cancer progenitor><cancer progenitor cells><cancer progression><cancer stem cell><carcinogenesis><cellular differentiation><chemotherapy><chromatin immunoprecipitation><combat><computational methodology><computational methods><computer based method><computer methods><computing method><cultured cell line><developmental><draining lymph node><driving><epigenetically><epigenomics><epithelial carcinoma><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><gene expression pattern><gene expression signature><gene signatures><genetic signature><genomic alteration><head and neck cancer patient><head and neck squamous carcinoma><head and neck squamous cell cancer><head/neck cancer><histone H3 methyltransferase><histone acetyltransferase><histone methylase><histone methyltransferase><human papillomavirus (-) head and neck squamous cell carcinoma><human papillomavirus - head and neck squamous cell carcinoma><human papillomavirus negative><human papillomavirus negative head and neck cancer><human papillomavirus negative head and neck squamous cell carcinoma><human papillomavirus- head and neck squamous cell carcinoma><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><insight><lymph node metastasis><mAbs><malignancy><malignant head and neck tumor><malignant mouth neoplasm><malignant mouth tumor><malignant progenitor><malignant stem cell><monoclonal Abs><mortality><mouse model><mouth SCC><mouth lesion><mouth squamous cell carcinoma><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><non-HPV HNSCC><non-human papillomavirus head and neck squamous cell carcinoma><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oral cavity SCC><oral cavity cancer><oral lesion><oral squamous cancer><oral squamous carcinoma><pathway><patient oriented outcomes><pharmacologic><progenitor cell gene><progenitor gene><prognostic ability><prognostic biomarker><prognostic power><prognostic utility><prognostic value><proto-oncogene protein c-erbB-1><recruit><regional lymph node><resistance to therapy><resistant><resistant to therapy><response><response to therapy><response to treatment><restoration><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecular inhibitor><small molecule><small molecule inhibitor><social role><stem cell characteristics><stem cell genes><stemness><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic response><therapy resistant><therapy response><trait><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><treatment resistance><treatment response><treatment responsiveness><tumor><tumor cell metastasis><tumor growth><tumor progression><tumor xenograft><αPD-1><αPD1><β-catenin>