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

基本信息

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
项目类别：
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

项目摘要

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是一种细胞命运 - 确定的转录因子，在〜70％的皮肤和头颈中表示患者的鳞状细胞癌（SCC）。 SOX2高度富含干细胞 - 样细胞肿瘤细胞（TPC），位于基底SCC层中，它们可以自我更新或分化为suprabasal SCC细胞没有增殖的潜力。尽管我们知道SOX2控制了TPC自我之间的命运选择更新和鳞状分化，尚不清楚其活性如何在SCC中调节可以将调节机制发展为癌症患者的疗法。在这里，我们建议测试假设Sox2抑制其活性，占SCC特异性SOX2-PITX1-的假设 TP63自我更新电路驱动克隆扩张和SCC增长，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辐射是否抑制了TPC自我更新，克隆扩张和SCC 生长; 2）确定调节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增长和分化的分子机制在鼠标和患者衍生的SCC模型中。我们希望我们提出的研究将解释胖子的选择在TPC的自我更新和终末分化之间，因此提供了新的概念为了合理发展药物方法，以实施TPC的承诺分化为SCC细胞而无需增殖。