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Histone modifications regulating phenotype plasticity: Role of non-canonical Wnt signaling

组蛋白修饰调节表型可塑性：非经典 Wnt 信号传导的作用

基本信息

批准号：
10248309
负责人：
Marie Ruth Webster
金额：
$ 24.9万
依托单位：
LANKENAU INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-05 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248309
关键词：
3-Dimensional Address Affect Automobile Driving Biological Assay Cell Cycle Cell Line Cell Maintenance Cell Proliferation Cells Characteristics Chromatin Clinical Data Development Drug resistance Dyes Epigenetic Process Exhibits Gene Expression Gene Silencing Generations Genetic Goals Growth Histone H3 Human Human Resources Hypermethylation In Vitro Invaded KDM5B gene Knowledge Lysine Maintenance Malignant Neoplasms Malignant neoplasm of prostate Melanoma Cell Membrane Mentors Metastatic Melanoma Methylation Methyltransferase Molecular Neoplasm Metastasis Nude Mice Pathway interactions Patients Pennsylvania Phenotype Plasmids Population Publishing Regulation Relapse Reporter Research Research Personnel Resistance Resources Role SETDB1 gene Signal Transduction Skin Skin Cancer Snails Stress Subcutaneous Injections The Wistar Institute Therapeutic Training Training Support Tumor Stem Cells Tumor Suppressor Genes Tumor Suppressor Proteins Tumorigenicity Universities WNT Signaling Pathway aggressive therapy base biological adaptation to stress cancer stem cell cancer type career career development cell motility chemotherapy design histone methylation histone methyltransferase histone modification in vivo in vivo imaging system inhibitor/antagonist insight knock-down malignant breast neoplasm melanocyte melanoma neoplastic cell novel therapeutic intervention pre-doctoral response self-renewal senescence skills small molecule stem stem-like cell subcutaneous success targeted treatment therapy resistant tumor tumor growth tumor progression

项目摘要

Project Summary The goals of this Pathway to Independence Career Development proposal are to request support for training to develop expertise in cancer epigenetics while addressing the role of slow cycling cells and histone modifications in phenotype plasticity of highly resistant metastatic melanoma. K99/R00 support during this part of my career will be integral to my successful development as an independent cancer researcher. The training plan outlined in this proposal will take advantage of the extensive resources at The Wistar Institute, University of Pennsylvania as well as Temple University. My training will also be guided by senior personnel who have successfully mentored predoctoral, postdoctoral, and clinical fellows in academic careers. The scientific portion of this proposal focuses on experimentally determining the molecular mechanism underlying phenotype plasticity and therapy resistance of invasive melanoma and the role of epigenetic changes in phenotype plasticity and maintenance of slow cycling cells. The proposed studies are based on my previous findings that a subset of melanoma cells, which express Wnt5A and p21, survive multiple types of stress by entering a slow-cycling, senescent-like state, but still invade and retain the ability to form metastases. My preliminary data suggest SEDTB1 expression correlates with an invasive phenotype in our human melanoma cell lines and driving non-invasive melanoma cells to a more invasive phenotype, through over expression of Wnt5A, increases SETDB1 expression. Expression of SETDB1, a histone methyltransferase, has been implicated in the silencing of tumor suppressor p16. p16 is expressed in melanocytes and early stages of melanoma but is lost during melanoma progression and this correlates with p21 expression and a senescent-like response following stress. In melanoma, hypermethylation during tumor progression is observed, which may block the expression of multiple tumor suppressor genes, but the role of specific epigenetic changes in phenotype plasticity and drug resistance is still largely unknown. Therefore, in line with these data I will explore the following scientific aims: 1) to elucidate the mechanism by which Wnt5A and p21 promote the maintenance of slow cycling stem-like cells;; and 2) to determine if histone modifications induced by SETDB1 promote phenotype plasticity and invasion in melanoma cells. The completion of the scientific aims in this proposal will develop my research skills and knowledge in cancer epigenetics while delineating the mechanism by which highly invasive resistant cells evade stress to promote melanoma metastasis and therapy resistance.

项目总结