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.

Public Health Relevance

Thyroid cancer is the most common form of endocrine malignancy with its incidence on steady rise. It is commonly an indolent disease, even though a small fraction of the patients will suffer from and succumb to a more aggressive form of disease with distant metastasis and higher mortality. In 2014 an estimated 62,980 new cases of thyroid cancer were diagnosed, while only 1,890 patients were projected to die from it. Unfortunately, there are no effective methods to differentiate the more aggressive cancers from those indolent ones, and as a result, most of the patients are treated with rather aggressive standard treatments, resulting in unnecessary morbidity and costs for most of the thyroid cancer patients. Ironically, the standard treatment is not effective against the truly aggressive form of thyroid cancer. In this research, we seek to improve the unsatisfactory status of thyroid cancer management by finding candidates molecular markers and treatment target for the more aggressive forms of thyroid cancer, especially those with distant metastasis. This is being accomplished by creation of a model of advanced thyroid cancer with distant metastasis by randomly inserting a mobile DNA element, known as transposons, across mouse genome leading to oncogenic mutations. By analysis of the mutations in harvested thyroid cancers, including lesions of distant metastasis, we'll be able to identify the genes important for the metastatic process, which can in turn be used for the desired molecular markers and treatment targets, once validated in separate experiments. In addition, the insertion sites left by these transposons in the metastatic lesions can be used as footprints to trace their origin in the primary thyroid cancer, and would for the first time to allw us to uncover the clonal origins of these metastatic lesions in the primary thyroid cancer, allowing us to study the metastasis biology in detail, including resolving a longstanding dispute regarding the origin of metastatic behaviors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA201735-02
Application #
9199587
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Snyderwine, Elizabeth G
Project Start
2016-01-01
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455