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

• 批准号: 10589086
• 负责人: Manish Bais
• 金额: $ 65.91万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/10589086
• 关键词: Address; Animal Model; Attenuated; Biology; Breast; Carcinoma in Situ; Cells; Cessation of life; Chromatin; Clinical; Collaborations; Data; Development; Disease; Dysplasia; Environment; Enzymes; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelium; 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; Neoplasms; Nivolumab; Normal tissue morphology; Nuclear; Oral; Oral cavity; PD-1 inhibitors; Pathologic; Pathway interactions; Patients; Phenotype; Positioning Attribute; Proteomics; Publishing; Recurrence; Resistance; Role; STAT3 gene; Sampling; Signal Induction; 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; cancer stem cell; carcinogenesis; 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; pharmacologic; prevent; programmed cell death ligand 1; programmed cell death protein 1; programs; promoter; single-cell RNA sequencing; stem; stem cells; therapy resistant; translational study; treatment strategy; tumor; tumor progression

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.

抽象的 赖氨酸特异性脱甲基酶1（LSD1）是一种核组蛋白脱甲基酶。我们的工作表明LSD1表达 临床口服鳞状细胞癌（OSCC）的肿瘤等级和阶段逐渐增加。我们的长期 术语目标是根据初步研究评估进行性口腔恶性肿瘤中的LSD1机制 治疗应用。最近的初步研究表明，舌头有条件的LSD1缺失 发育异常期间上皮减少了侵入性病理病变，下调的EGFR，YAP诱导的信号传导 网络和PD-L1表达。接下来，发育异常期间LSD1抑制剂的局部应用阻止了其 发展为侵入性表型，衰减病变病变，河马信号效应子的表达（YAP， TAZ，CCN2）和免疫检查点（PD-1和PD-L1）。 LSD1抑制剂将OSCC敏感与与 YAP抑制剂，抗PD-1或抗PD-L1抗体，限制了体内肿瘤的进展。因此，我们表明 首次阻止LSD1抑制质量肿瘤，这是一个在进展过程中的前进环 发育异常到OSCC。有趣的是，LSD1抑制作用减弱了IL-6-JAK-STAT3新型信号传导 独立研究1）LSD基因敲除小鼠的蛋白质组学分析和2）单细胞RNASEQ 使用LSD1抑制剂进行分析。但是，LSD1功能的机理，其靶细胞进行性口服 恶性肿瘤以及LSD1如何促进IL-6-JAK-STAT3尚不清楚。这个知识差距阻止了 OSCC有效的新表观遗传治疗策略的有针对性设计。我们假设（1）LSD1 发育不良期间的上调通过作用于IL6信号和 诱导细胞类型和（2）LSD1复位表观组的药理衰减以反向进行性 恶性肿瘤对非侵入性表型。使用临床相关的动物模型，该项目很好 定位以解决以下特定目的：1）确定如何表观上调LSD1 重编程发育不良，以促进进行性口服肿瘤浸润性表型期间促进IL6网络； 2）到 确定LSD1是否与YAP合作以促进IL6-JAK-STAT3网络引起的侵入性表型 肿瘤和3）确定药理学LSD1抑制的翻译重要性反向 通过抑制IL6-JAK-STAT3信号传导诱导癌症和免疫细胞的肿瘤质量。成功 预计该项目的完成将确定LSD1和治疗应用机制 IL6-JAK-STAT3网络，相关的干细胞和免疫细胞。最后，研究将确定LSD1是否作用 在抗PD-1免疫疗法中，耐药性和药理学LSD1抑制作用可以减弱猫OSCC 兽医和人类医学中的潜在应用。总体而言，这项研究将对未来产生更大的影响 人类肿瘤的翻译研究。