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Mechanism of LSD1 Function and Its Therapeutic Application for Progressive Oral Malignancy

LSD1的功能机制及其在进行性口腔恶性肿瘤的治疗中的应用

基本信息

批准号：
10357374
负责人：
Manish Bais
金额：
$ 57.02万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10357374
关键词：
Address Animal Model Attenuated Biology Breast Carcinoma in Situ Cells Cessation of life Chromatin Clinical Data Development Disease Dysplasia Environment Enzymes Epidermal Growth Factor Receptor Epigenetic Process Epithelial Family Felidae Future Genetic Goals Human IL-6 inhibitor IL6 gene Immune Immunotherapy Interleukin-6 JAK2 gene KDM1A gene Keratin Knockout Mice Knowledge Lead Lesion Leukoplakia Malignant - descriptor Malignant Neoplasms Medicine Modification Mus Nivolumab Normal tissue morphology Nuclear Oral Oral cavity Pathologic Pathway interactions Patients Pharmacology Phenotype Positioning Attribute Proteomics Publishing Recurrence Resistance Role STAT3 gene Sampling Signal Transduction Testing Therapeutic Therapeutic Studies Time Tissue Sample Tongue Topical application Translations United States Up-Regulation Work anti-PD-1 anti-PD-L1 antibodies anti-PD1 therapy anticancer research attenuation base cancer stem cell cell type clinically relevant connective tissue growth factor design effective therapy epigenome experience high risk histone demethylase immune checkpoint in vivo inhibitor malignant mouth neoplasm malignant phenotype mouse model mouth squamous cell carcinoma novel oral tissue patient derived xenograft model prevent programmed cell death ligand 1 programmed cell death protein 1 promoter single-cell RNA sequencing stem stem cells therapy resistant translational study treatment strategy tumor tumor progression

项目摘要

Abstract Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase. Our work shows that LSD1 expression progressively increases with tumor grade and stage in clinical oral squamous cell carcinoma (OSCC). Our long- term goal is to evaluate LSD1 mechanism in progressive oral malignancy based on preliminary studies for therapeutic applications. Recent preliminary studies showed that conditional LSD1 deletion in the tongue epithelium during dysplasia reduced invasive pathological lesions, downregulated EGFR, YAP-induced signaling network, and Pd-L1 expression. Next, the topical application of LSD1 inhibitor during dysplasia prevented its progression to invasive phenotype, attenuated pathological lesions, expression of Hippo signaling effectors (Yap, Taz, Ccn2,) and immune checkpoints (Pd-1, and Pd-l1). LSD1 inhibitor sensitized OSCC to combinations with either YAP inhibitor, anti-PD-1, or anti-PD-L1 antibodies, limiting tumor progression in vivo. Thus, we showed for the first time that blocking LSD1 inhibits preneoplasia, a feed-forward loop during the progression of dysplasia to OSCC. Interestingly, LSD1 inhibition attenuates IL-6-JAK-STAT3 novel signaling identified in two independent studies 1) proteomics analysis of LSD knockout mice preneoplasia and 2) single-cell RNAseq analysis using LSD1 inhibitor. However, the mechanism of LSD1 function, its target cells in progressive oral malignancy, and how LSD1 promotes IL-6-JAK-STAT3 remain unclear. This knowledge gap prevents the targeted design of effective new epigenetic therapeutic strategies for OSCC. We hypothesize that (1) LSD1 upregulation during dysplasia reprograms oral tissue to invasive phenotype by acting on IL6 -signaling and induced cell types and (2) pharmacological attenuation of LSD1 reset epigenome to reverse progressive malignant preneoplasia to a noninvasive phenotype. Using clinically relevant animal models, this project is well- positioned to address the following Specific Aims: 1) to determine how upregulated LSD1 epigenetically reprogram dysplasia to promote IL6 network during progressive oral preneoplasia invasive phenotype; 2) to determine if LSD1 collaborates with YAP to promote IL6-JAK-STAT3 network induced invasive phenotype in preneoplasia, and 3) to determine the translational importance of pharmacological LSD1 inhibition reverse preneoplasia by inhibiting IL6-JAK-STAT3 signaling induced cancer stem and immune cells. The successful completion of the proposed project is expected to identify LSD1 and therapeutic application mechanisms in the IL6-JAK-STAT3 network, related stem cells, and immune cells. Finally, the study will determine if LSD1 a role in anti-PD-1 immunotherapy resistance and pharmacological LSD1 inhibition can attenuate feline OSCC for a potential application in veterinary and human medicine. Overall, the study will have a broader impact on future translational studies in human preneoplasia.

摘要