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:
- 金额:$ 57.02万
- 依托单位:
- 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:
- 关键词:AddressAnimal ModelAttenuatedBiologyBreastCarcinoma in SituCellsCessation of lifeChromatinClinicalDataDevelopmentDiseaseDysplasiaEnvironmentEnzymesEpidermal Growth Factor ReceptorEpigenetic ProcessEpithelialFamily FelidaeFutureGeneticGoalsHumanIL-6 inhibitorIL6 geneImmuneImmunotherapyInterleukin-6JAK2 geneKDM1A geneKeratinKnockout MiceKnowledgeLeadLesionLeukoplakiaMalignant - descriptorMalignant NeoplasmsMedicineModificationMusNivolumabNormal tissue morphologyNuclearOralOral cavityPathologicPathway interactionsPatientsPharmacologyPhenotypePositioning AttributeProteomicsPublishingRecurrenceResistanceRoleSTAT3 geneSamplingSignal TransductionTestingTherapeuticTherapeutic StudiesTimeTissue SampleTongueTopical applicationTranslationsUnited StatesUp-RegulationWorkanti-PD-1anti-PD-L1 antibodiesanti-PD1 therapyanticancer researchattenuationbasecancer stem cellcell typeclinically relevantconnective tissue growth factordesigneffective therapyepigenomeexperiencehigh riskhistone demethylaseimmune checkpointin vivoinhibitormalignant mouth neoplasmmalignant phenotypemouse modelmouth squamous cell carcinomanoveloral tissuepatient derived xenograft modelpreventprogrammed cell death ligand 1programmed cell death protein 1promotersingle-cell RNA sequencingstemstem cellstherapy resistanttranslational studytreatment strategytumortumor 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.
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。
项目成果
期刊论文数量(0)
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Manish Bais其他文献
Manish Bais的其他文献
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{{ truncateString('Manish Bais', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 57.02万 - 项目类别:
Epigenetic targeting of LSD1 for OSCC Therapy
用于 OSCC 治疗的 LSD1 表观遗传靶向
- 批准号:
9766270 - 财政年份:2018
- 资助金额:
$ 57.02万 - 项目类别:
LOXL2 in Temporomandibular Joint Osteoarthritis
LOXL2 在颞下颌关节骨关节炎中的作用
- 批准号:
9100747 - 财政年份:2015
- 资助金额:
$ 57.02万 - 项目类别:
LOXL2 in Temporomandibular Joint Osteoarthritis
LOXL2 在颞下颌关节骨关节炎中的作用
- 批准号:
8951806 - 财政年份:2015
- 资助金额:
$ 57.02万 - 项目类别:
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