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Principal Investigator: Chao Lu
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $444,406
Funding agency: National Institute of Dental and Craniofacial Research
PROJECT SUMMARY
Head and Neck Squamous Cell Carcinomas (HNSCC) affect ~60,000 individuals in the US every year. Despite
aggressive treatment, the 5-year survival rate for HNSCC remains ~50% and frequently patients suffer relapse
and the development of metastatic lesions. Our previous work showed that NSD1, a histone methyltransferase
that specifically catalyzes di-methylation of histone H3 Lys36 (H3K36me2), is frequently inactivated in HNSCC.
Deletions, mutations and biochemical inhibition of NSD1 by the oncohistone H3K36M mutation are found in 15%
of HNSCC and define a novel disease subgroup with distinct molecular and clinical features. However, the
mechanism by which NSD1 inactivation promotes HNSCC development remains unclear. We recently reported
that NSD1 inactivation in HNSCC cell lines and patient samples resulted in profound DNA hypomethylation. Our
preliminary studies further demonstrated that NSD1 mutations in HNSCC are associated with increased genomic
instability and retrotransposon de-repression. Intriguingly, these molecular events are known to promote tumor
recognition by host immune system, yet NSD1 mutant tumors are unexpectedly immune “cold” with minimal
presence of tumor-infiltrating leukocytes and a reduced interferon response. Therefore, we propose to test the
hypothesis that NSD1 inactivation in HNSCC reduces tumor immunogenicity and facilitates immune evasion
through epigenetic silencing of the interferon signaling pathway. In Aim 1, we will define the role of NSD1 in
HNSCC immune evasion in vivo. We plan to employ syngeneic and genetically engineered mouse models of
HNSCC driven by NSD1 loss that have been developed in our lab. Together with the state-of-the-art single-cell
RNA-seq and multiplex imaging technologies, we will examine the changes in tumor microenvironment following
NSD1 loss. In Aim 2, we will study epigenetic mechanisms by which NSD1 regulates interferon response. We
propose to test the model that NSD1 antagonizes H3K27 tri-methylation (H3K27me3), a repressive histone mark
catalyzed by EZH2, to maintain STAT1 expression. In Aim 3, using syngeneic and humanized mouse models,
we will test if pharmacological inhibition of EZH2 can restore immune infiltration and delay the growth of NSD1-
deficient tumors alone or in combination with immune checkpoint inhibitor. Since only a minority of HNSCC
patients respond to immune checkpoint inhibitors, our expected results will have immediate translational
implication by nominating (1) NSD1/H3K36me2 as biomarkers for predicting therapeutic response to
immunotherapy and (2) an FDA-approved EZH2 inhibitor which can be combined with checkpoint inhibitors to
target poorly infiltrated, immune “cold” tumors. More broadly, this project will also contribute to our understanding
of chromatin-based mechanisms exploited by cancer cells to facilitate immune evasion.
Terms: <Ablation><Affect><Biochemical><Biological Markers><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Line><CellLine><Checkpoint inhibitor><Chromatin><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><DNA><DNA Methyltransferase><DNA Modification Methylases><DNA Modification Methyltransferases><DNA-Methyltransferases><DNMT3a><Deoxyribonucleic Acid><Development><Disease><Disorder><Dnmt><ENX-1><EZH1><EZH2><EZH2 gene><Elements><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><FDA approved><Future><GEM model><GEMM model><Gene Action Regulation><Gene Down-Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetically Engineered Mouse><Genome Instability><Genomic Instability><Growth><HNSCC><Head and Neck Cancer><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Histone H3><Histones><IFN><Imaging technology><Immune><Immune Evasion><Immune Surveillance><Immune Targeting><Immune checkpoint inhibitor><Immune infiltrates><Immune mediated therapy><Immune system><Immunes><Immunocompetent><Immunofluorescence><Immunofluorescence Immunologic><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunosurveillance><Immunotherapy><Incidence><Individual><Infiltration><Interferons><KMT6><KMT6A><Knowledge><Leucocytic infiltrate><Link><Malignant Cell><Malignant Head and Neck Neoplasm><Mediating><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methylation><Mice><Mice Mammals><Minority><Modeling><Modification Methylases><Molecular><Murine><Mus><Mutation><Nature><Neoplasm Metastasis><Patients><Pattern recognition receptor><Prediction of Response to Therapy><Recurrence><Recurrent><Regulation><Relapse><Reporting><Resistance><Retrotransposon><Role><SCCHN><STAT1><STAT1 gene><STAT91><Sampling><Science><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Site-Specific DNA-methyltransferase><Strains Cell Lines><Survival Rate><Technology><Testing><Therapeutic><Therapeutic Effect><Tissue Growth><Tissue imaging><Transcription Repression><Transcriptional Repression><Tumor Escape><Tumor Immune Escape><Tumor Promotion><Tumor-infiltrating immune cells><Work><advanced disease><advanced illness><aggressive therapy><aggressive treatment><bio-markers><biologic marker><biomarker><cancer cell><cancer evasion><cancer immune escape><cancer immune evasion><cancer metastasis><cancer microenvironment><cancer progression><cultured cell line><derepression><developmental><disease subgroups><disease subtype><disorder subtype><epigenetic gene silencing><epigenetic regulation><epigenetic silencing><epigenetically><epigenome><gain of function><gene repression><genetically engineered mouse model><genetically engineered murine model><genome mutation><genome scale><genome-wide><genomewide><hDNA methyltransferase 3a><head and neck squamous carcinoma><head and neck squamous cell cancer><head/neck cancer><histone H3 methyltransferase><histone methylase><histone methyltransferase><humanized mice><humanized mouse><immune cell infiltrate><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point inhibitor><immune competent><immune evasive><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenicity><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><infiltration of tumors by immune cells><inhibitor><intratumoral immune cell><intratumoral immune infiltrate><loss of function><malignant head and neck tumor><mouse model><multiplexed imaging><murine model><mutant><neoplasm progression><neoplastic progression><novel><oncohistone><ontogeny><patient response><patient specific response><pharmacologic><predict therapeutic response><predict therapy response><predictive biomarkers><predictive marker><predictive molecular biomarker><recruit><resistant><response><responsive patient><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><therapeutic target><therapy prediction><treatment prediction><treatment response prediction><tumor><tumor cell metastasis><tumor evasion><tumor immune cell><tumor immune evasion><tumor immune infiltrate><tumor infiltration of immune cells><tumor microenvironment><tumor progression>