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Searching for Genetic Basis for Metastasis of Differentiated Thyroid Cancer

寻找分化型甲状腺癌转移的遗传基础

基本信息

批准号：
9020692
负责人：
DAVID ANDREW LARGAESPADA
金额：
$ 16.62万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020692
关键词：
Address Age Aggressive behavior Algorithms Antisense RNA Area Behavior Biological Assay Biology Breeding Cancer Patient Candidate Disease Gene Cells Clinical Complement Coupled DNA Detection Diagnosis Disease Disputes Distant Metastasis Elements Endocrine Fluorescent in Situ Hybridization Fright Frozen Sections Future Genes Genetic Genetic Determinism Growth Harvest High Prevalence Human Hybrids In Vitro Incidence Individual Indolent Injection of therapeutic agent Insertional Mutagenesis Lasers Left Lesion Lung Malignant Neoplasms Malignant neoplasm of thyroid Maps Mediating Methods Modeling Molecular Profiling Morbidity - disease rate Mus Mutagenesis Mutation Mutation Analysis Neoplasm Metastasis Oncogenic Organ Outcome Pathway interactions Patient Triage Patients Phenotype Population Primary Neoplasm Property RNA RNA Probes Reading Research Rest Risk Sampling Shapes Site Sleeping Beauty Stratification Testing Thyroid Gland Time Validation Xenograft procedure advanced disease base cancer cell cancer genetics carcinogenesis cohort comparative genomics cost deep sequencing design effective therapy high risk improved in vivo loss of function mutation meetings metastatic process molecular marker mortality mouse genome mouse model novel public health relevance research study standard care thyroid neoplasm tissue/cell culture trait transcriptome sequencing transposon/insertion element tumor

项目摘要

DESCRIPTION (provided by applicant): Thyroid cancer is the most common endocrine malignancy. Most of the patients have an indolent course, but for fear of more aggressive diseases such as distant metastasis, have nonetheless been treated with over-aggressive standard treatment, which ironically is not really effective towards those truly aggressive forms of thyroid cancer. Better understanding of the genetic basis of distant metastasis is essential for more accurate risk stratification and more effective treatment, but this effort has been limited by the lack of clinical samples. Our research group has previously established a method to use Sleeping Beauty (SB) transposon- based random insertional mutagenesis for study of cancer genetics. Using this method, we have recently created a mouse model of advanced thyroid cancer with a high incidence for distant metastasis. In the research proposed here, we will use this model to answer a fundamental question regarding how metastatic phenotypes originate from the primary DTC and test the hypothesis that the metastatic traits take shape in a subpopulation of cells in the primary tumor from newly acquired mutations which offer selection advantage for distant metastasis (clonal selection model). This question will mainly be addressed by comparing the SB insertion sites in the primary tumors and the metastatic lesions. The first aim attempts to isolate the clonal origin of a metastatic lesion in the primary tumor, after establishing unique clonal SB insertion sites in the metastatic lesion as its molecular signature, and then determine if this clone has acquired any novel phenotypes that favor metastasis by studying its expression profile. The second aim will analyze the SB insertion sites at the population level in both primary and metastatic DTC to decide if there are any common insertion sites (CIS) specific for metastatic lesion (met-CIS), which would indicate newly acquired mutations and phenotypes in the metastatic lesions, or CISs enriched in primary tumors with significant metastasis (premet-CIS), which would suggest genes/pathways predisposing to metastasis when altered in the primary tumor. Also in third aim, we will try to validate the genes associated with metastasis found in the aim #2 by looking for their alterations in advanced human thyroid cancer samples, and test their oncogenic and metastatic properties in vitro and in vivo. The results of these experiments will be the basis of the future translationa research to develop molecular markers and treatment targets for metastatic thyroid cancer.