Our long-term goal is to understand mechanisms of tumor progression and metastasis and to develop new approaches for molecularly targeted therapeutics. Metastasis, a multi-step process in which primary tumor cells disseminate to distant sites of the body and form secondary tumors, is the leading cause of cancer deaths and remains one of the most poorly understood pathological processes. New biomarkers of metastatic diseases and useful targets for therapeutic intervention, including proteins, microRNAs, and other non-coding RNAs, continue to be highly sought. We and others have demonstrated the existence of metastasis-promoting and metastasis-suppressing microRNAs. Moreover, we provided proof-of-concept evidence that antagomirs targeting a pro-metastatic microRNA can be efficiently delivered to fast growing tumor cells in vivo and can block metastasis formation by otherwise highly malignant cells. The molecular mechanisms by which these individual microRNAs function in metastatic progression warrant further investigation. In this application: 1) we will identify and characterize the functional targets of metastasis-promoting microRNAs. Combining high- throughput RNA sequencing, computational approach, functional experiments, mechanistic analysis, and patient studies, we will investigate a microRNA target that represents a novel suppressor of metastasis. 2) We will study how two distinct metastasis-regulating microRNAs are connected. Our preliminary data demonstrated that expression of a specific metastasis-promoting microRNA (miR-9) leads to downregulation of the primary transcript but upregulation of the mature form of another pro-metastatic microRNA (miR-10b). Subsequently, we will investigate the mechanisms by which miR-9 regulates miR-10b biogenesis and determine whether miR-10b is required for mediating miR-9-induced metastasis. 3) We will identify and characterize new epithelial-mesenchymal transition (EMT)-regulating microRNAs. By conducting microRNA expression profiling analysis of cells that have undergone EMT, we have recently identified a microRNA signature of EMT, and discovered that two microRNAs in this signature function as EMT inducers. We will determine the mechanisms by which these two microRNAs induce EMT and whether they regulate tumor metastasis and stem cell properties. The knowledge gained from these studies will fundamentally advance our current understanding of how microRNAs and their targets regulate metastasis and EMT and may have important clinical implications.

Public Health Relevance

MicroRNAs are beginning to be implicated in tumor progression and metastasis, and they act by suppressing the expression of target genes. In this grant application, we will study the regulation of tumor metastasis and epithelial-mesenchymal transition by specific microRNAs and their target genes. These studies will reveal the molecular mechanisms underlying malignant progression and new targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166051-03
Application #
8676742
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2012-08-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$318,015
Indirect Cost
$116,740
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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