Post-translational SOX2 modification - a regulatory switch between self-renewal and differentiation in squamous cell carcinoma

翻译后 SOX2 修饰 - 鳞状细胞癌自我更新和分化之间的调节开关

• 批准号: 10532795
• 负责人: Markus Schober
• 金额: $ 45.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532795
• 关键词: Ablation; Acceleration; Affect; Androgens; Attenuated; Biological Assay; CDK5 gene; Cancer Patient; Cell Nucleus; Cells; ChIP-seq; Chromatin; Clonal Expansion; Co-Immunoprecipitations; Complex; Cutaneous; Data; Development; Disease; Enhancers; Epithelial Cells; Gene Expression; Genetic Transcription; Glioblastoma; Growth; Head and Neck Squamous Cell Carcinoma; Human; Immune checkpoint inhibitor; Knock-in Mouse; Ligation; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Modeling; Modification; Molecular; Mus; Mutation; Oncogenic; Patients; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Publishing; Recurrence; Regulation; Regulator Genes; Repression; Research; Resected; Resistance; Skin; Squamous Cell Lung Carcinoma; Squamous Differentiation; Squamous cell carcinoma; Testing; Therapeutic immunosuppression; United States; Western Blotting; cancer therapy; carcinogenesis; mimetics; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; organ transplant recipient; osteosarcoma; patient derived xenograft model; pharmacologic; phosphatase inhibitor; prevent; programs; self-renewal; single molecule; stem-like cell; tandem mass spectrometry; transcription factor; tumor

SUMMARY SOX2 is a cell fate–determining transcription factor that is expressed in ~70% of cutaneous and head and neck squamous cell carcinomas (SCCs) in patients. SOX2 is highly enriched in stem cell–like tumor-propagating cells (TPCs), which are located within the basal SCC layer where they can self-renew or differentiate into suprabasal SCC cells without proliferative potential. Although we know SOX2 controls the fate choice between TPC self- renewal and squamous differentiation, it is unclear how its activity is regulated in SCCs and whether these regulatory mechanisms could be developed into therapies for cancer patients. Here, we propose to test the hypothesis that phosphorylation of SOX2 inhibits its activity, perturbs the SCC-specific SOX2-PITX1- TP63 self-renewal circuit that drives clonal expansion and SCC growth, and thereby restores the KLF4- dependent squamous differentiation program in SCCs. Our hypothesis is based on our preliminary studies, which showed that SOX2 can be phosphorylated and that this phosphorylation attenuates its activity in SCC cells. We propose to 1) test if SOX2 phosphorylation inhibits TPC self-renewal, clonal expansion, and SCC growth; 2) identify the kinases and phosphatases that regulate SOX2 phosphorylation and function; and 3) define the molecular mechanisms by which SOX2 activity governs TPC self-renewal, SCC growth, and differentiation in mouse and patient-derived SCC models. We expect our proposed research will explain the fate choice between TPC self-renewal and terminal differentiation on a molecular level and therefore provide new concepts for the rational development of pharmacological approaches that enforce the commitment of TPCs to terminally differentiate into SCC cells without proliferative potential.

概括 SOX2 是一种决定细胞命运的转录因子，在约 70% 的皮肤和头颈部表达 患者的鳞状细胞癌（SCC）。 SOX2 在干细胞样肿瘤增殖细胞中高度富集 （TPC），位于基底 SCC 层内，可以自我更新或分化为基底上层 SCC细胞无增殖潜力。尽管我们知道SOX2控制着TPC自我之间的命运选择 更新和鳞状分化，目前尚不清楚其活性在 SCC 中是如何调节的以及这些是否 调节机制可以开发成癌症患者的疗法。在这里，我们建议测试 假设 SOX2 的磷酸化会抑制其活性，扰乱 SCC 特异性 SOX2-PITX1- TP63 自我更新电路可驱动克隆扩增和 SCC 生长，从而恢复 KLF4- SCC 中的依赖性鳞状分化程序。我们的假设是基于我们的初步研究， 这表明 SOX2 可以被磷酸化，并且这种磷酸化减弱了其在 SCC 中的活性 细胞。我们建议 1) 测试 SOX2 磷酸化是否抑制 TPC 自我更新、克隆扩增和 SCC 生长; 2) 鉴定调节SOX2磷酸化和功能的激酶和磷酸酶； 3）定义 SOX2 活性控制 TPC 自我更新、SCC 生长和分化的分子机制 在小鼠和患者衍生的鳞状细胞癌模型中。我们希望我们提出的研究能够解释命运的选择 在分子水平上区分TPC自我更新和终末分化，从而提供新概念 合理开发药理学方法，强化 TPC 对最终治疗的承诺 分化为没有增殖潜力的鳞状细胞癌（SCC）细胞。