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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：
10308508
负责人：
Markus Schober
金额：
$ 44.17万
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/10308508
关键词：
Ablation 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 Pharmacology Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Plant Roots Publishing Recurrence Regulation Regulator Genes Research Resected Resistance Skin Squamous Cell Lung Carcinoma Squamous Differentiation Squamous cell carcinoma Testing Therapeutic immunosuppression United States Western Blotting base cancer therapy carcinogenesis mimetics mouse model mutant new therapeutic target novel novel therapeutic intervention novel therapeutics organ transplant recipient osteosarcoma patient derived xenograft model 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.

总结