Characterizing the Role of Leucyl Aminoacyl tRNA Synthetase (LARS) in Breast Cancer Metastasis

表征亮氨酰 tRNA 合成酶 (LARS) 在乳腺癌转移中的作用

• 批准号: 9909283
• 负责人: Maria Christina Passarelli
• 金额: $ 5.05万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-09 至 2023-12-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909283
• 关键词: Academic Medical Centers; Acids; Affect; Amino Acids; Amino Acyl-tRNA Synthetases; Aminoacylation; Attenuated; Biogenesis; Biological Assay; Biology; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast cancer metastasis; Cancer Biology; Cancer Etiology; Cancer Prognosis; Cell Line; Cell physiology; Cells; Charge; Clinical; Committee Members; Communication; Data; Development; Diagnosis; Disease; Doctor of Philosophy; Elements; Ensure; Environment; Enzymes; Foundations; Future; Genes; Genetic; Genetic Translation; Human; In Vitro; Internal Medicine; Knock-out; Knockout Mice; Knowledge; Leucine; Leucine-Specific tRNA; Literature; Malignant Neoplasms; Mediating; Medical; Mentors; Mentorship; Metastasis Suppression; Metastatic breast cancer; Modeling; Molecular; Molecular Target; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Play; Process; Proteins; Proteomics; RNA; Research; Research Personnel; Residencies; Resources; Ribosomal RNA; Rice; Role; Scientist; Soft Agar Assay; Solid; Testing; Therapeutic; Training; Transfer RNA; Transfer RNA Aminoacylation; Translations; Tumor Biology; Tumor stage; Universities; Untranslated RNA; Woman; Work; Xenograft procedure; base; cancer cell; cancer subtypes; cell growth; combat; comparative; doctoral student; in vitro Assay; in vivo; insight; knock-down; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; outcome forecast; overexpression; programs; ribosome profiling; skills; small hairpin RNA; therapeutic target; transcriptome sequencing; tumor; tumor initiation; tumor progression

PROJECT SUMMARY/ABSTRACT Breast cancer metastasis is a leading cause of mortality in US women. Despite advances in treatment for patients with early stage tumors, prognosis remains poor for patients with metastatic disease. Prior work has demonstrated a direct role for transfer RNAs (tRNAs) as drivers of breast cancer metastatic progression, through differential abundance resulting in changes in cell proteomic landscape. I hypothesize that aminoacylation status, as in, whether or not a tRNA is charged with an amino acid, and the requisite aminoacyl tRNA synthetase (aaRS) responsible for tRNA charging, will also play a role in breast cancer metastatic progression. To test this hypothesis, charged tRNAs were profiled across cells of differing metastatic potential, which identified key reductions in leucine tRNA charging in cells of higher metastatic potential. Preliminary xenograft and syngeneic mouse metastasis studies further identified leucyl aaRS (LARS), responsible for charging leucine tRNAs, as a metastasis suppressor. In this proposal, I will examine and further characterize the role of LARS in cancer metastasis. In Aim 1, I will further characterize the effects of LARS manipulation (1) through knockdown and overexpression in xenograft and syngeneic cancer mouse models, and (2) through genetic knockout in mouse models of breast cancer. In Aim 2, I will investigate (1) the cellular phenotype of metastasis suppression through in vitro assays and (2) the mechanism of charged tRNA-mediated metastasis suppression through downstream RNA sequencing analysis and ribosomal profiling. These proposed studies will fill a gap in literature: though tRNAs play a role in cancer progression, molecules related to their biogenesis have yet to be identified as therapeutically meaningful targets in cancer metastasis. Successful completion of these aims will lay the groundwork for future therapeutic targets with novel mechanisms, in treating metastatic breast cancer. I am an MD-PhD student at the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD program, completing the proposed aims in the lab of Dr. Sohail Tavazoie at Rockefeller University. Dr. Tavazoie, along with my committee members Drs. Charles Rice, Ping Chi and Kivanc Birsoy, provide strong scientific expertise, guidance and resources to ensure successful completion of the project. Together, we have taken steps to ensure my training plan also allows for development of necessary verbal and written communication skills as well as mentorship opportunities. My clinical mentors, Drs. Pamela Charney and Ping Chi, will offer critical advice on maintaining clinical acumen as I transition towards completion of medical training and select research-track residency programs in Internal Medicine. Successful completion of the proposed plan in this stellar training environment will enhance my foundational knowledge of RNA biology and teach me skills in cancer biology and mouse modeling, setting me solidly on the path towards becoming a physician scientist and independent investigator at an academic medical center.

项目总结/文摘