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in vivo CRISPR screen of SLC transporters to identify metabolic requirements of metastasis

Despite the recent progresses in breast cancer diagnosis and therapy, breast cancer metastasis still accounts for 90% of all patient deaths. Recent studies show that cancer cells rewire their metabolism to the available nutrients to answer the drastic changes in the environment during metastasis. Therefore, I hypothesize that solute nutrient transporter (SLC), the largest family of nutrient transporters, play a key role in the delivery of nutrients to cancer cells that are essential for metastasis formation in distant organs. Consequently, I expect that the disruption of the SLC expression will reveal specific metabolic dependencies of metastatic growth. During this study, I will conduct a CRISPR/Cas9 loss-of-function screen to knockout 407 SLC proteins in the spontaneously metastasizing 4T1 breast cancer mouse model. Afterwards I will sequence the metastases in lung and liver and identify which SLC transporters nutrients fuel metastasis in these specific sites. After validation in both 4T1 as EMT6.5 mouse models, I will perform functional metabolomics studies in vitro to determine the mechanism of action by which these nutrients are essential in metastasis formation. I expect that this project will identify novel mechanisms by which nutrients are used during the progress of metastases formation. This study will reveal new drug targets for the targeted prevention and treatment of breast cancer metastasis in the lung and liver. 

Date:1 Oct 2020 →  Today
Keywords:Metabolism, Breast cancer, Metastasis
Disciplines:Cancer biology
Project type:PhD project