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: 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
• 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

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 赖氨酸特异性去甲基化酶 1 (LSD1) 是一种核组蛋白去甲基化酶。我们的工作表明 LSD1 表达 在临床口腔鳞状细胞癌（OSCC）中，随着肿瘤分级和分期的进行而逐渐增加。我们的长期 短期目标是根据以下初步研究评估 LSD1 在进行性口腔恶性肿瘤中的作用机制： 治疗应用。最近的初步研究表明，舌头中条件性LSD1缺失 上皮细胞发育不良期间减少了侵袭性病理病变，下调了 EGFR、YAP 诱导的信号传导 网络和 Pd-L1 表达。接下来，在发育异常期间局部应用 LSD1 抑制剂可防止其发生。 进展为侵袭性表型、病理病变减弱、Hippo 信号效应子表达（Yap、 Taz、Ccn2) 和免疫检查点（Pd-1 和 Pd-l1）。 LSD1 抑制剂使 OSCC 对其组合敏感 YAP 抑制剂、抗 PD-1 或​​抗 PD-L1 抗体，限制体内肿瘤进展。因此，我们展示了 首次阻断 LSD1 抑制肿瘤前期，这是肿瘤进展过程中的一个前馈循环 发育不良至 OSCC。有趣的是，LSD1 抑制减弱了在两种药物中发现的 IL-6-JAK-STAT3 新信号传导 独立研究 1) LSD 敲除小鼠肿瘤前期的蛋白质组学分析和 2) 单细胞 RNAseq 使用LSD1抑制剂进行分析。然而，LSD1的功能机制及其在渐进性口腔中的靶细胞 恶性肿瘤，以及 LSD1 如何促进 IL-6-JAK-STAT3 仍不清楚。这种知识差距阻碍了 有针对性地设计有效的新表观遗传学治疗 OSCC 策略。我们假设 (1) LSD1 不典型增生期间的上调通过作用于 IL6 信号传导将口腔组织重新编程为侵袭性表型 诱导细胞类型和 (2) LSD1 的药理学减弱重置表观基因组以逆转进展 恶性癌前病变转变为非侵袭性表型。使用临床相关的动物模型，该项目很好- 定位于解决以下具体目标：1) 确定 LSD1 如何在表观遗传上上调 在进行性口腔癌前期侵袭性表型期间，重新编程发育不良以促进 IL6 网络； 2）到 确定 LSD1 是否与 YAP 合作促进 IL6-JAK-STAT3 网络诱导的侵袭表型 肿瘤前期，以及 3) 确定药理学 LSD1 抑制逆转的转化重要性 通过抑制 IL6-JAK-STAT3 信号诱导癌症干细胞和免疫细胞形成癌前病变。成功者 拟议项目的完成预计将确定 LSD1 和治疗应用机制 IL6-JAK-STAT3网络、相关干细胞和免疫细胞。最后，该研究将确定 LSD1 是否发挥作用 抗 PD-1 免疫治疗耐药性和药理学 LSD1 抑制可以在一定程度上减轻猫科动物 OSCC 在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广泛的影响 人类肿瘤前期的转化研究。