A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.
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2024-05
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Abstract
Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here we report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumours. We applied this platform to identify the transporters of amino acids in leukaemia cells and found that amino acid transport involves high bidirectional flux dependent on the microenvironment composition. While investigating the role of transporters in cystine starved cells, we uncovered a role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumours and found that levels of glucose and amino acids can restrain proliferation in that environment. This study establishes a framework for systematically identifying critical cellular nutrient transporters, characterizing their function and exploring how the tumour microenvironment impacts cancer metabolism.
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Chidley, Christopher, Alicia M Darnell, Benjamin L Gaudio, Evan C Lien, Anna M Barbeau, Matthew G Vander Heiden and Peter K Sorger (2024). A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments. Nature cell biology, 26(5). pp. 825–838. 10.1038/s41556-024-01402-1 Retrieved from https://hdl.handle.net/10161/31262.
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Christopher Chidley
Chris Chidley is an incoming Assistant Professor in the Department of Pharmacology and Cancer Biology starting in September 2024.
The Chidley lab investigates the role of transporter proteins in nutrient and metabolite import/export and their impact on cell state and response to chemotherapeutics. The lab uses unbiased genetic screening in cell and animal models along with biochemistry, cell biology, and analytical chemistry tools to identify critical small molecule transporters across different environments, characterize their function, and explore how the tumor microenvironment impacts cancer metabolism. Our research aims to guide the development of metabolic strategies to suppress tumor growth, and aid precision medicine efforts by revealing determinants of drug sensitivity.
For more information, visit our lab website.
Alicia Darnell
Incoming Assistant Professor in Pharmacology and Cancer Biology (Sept 2024).
Lab website: https://sites.duke.edu/darnelllab/
Protein synthesis is a critical integration point for cellular metabolism, growth, and gene expression. The Darnell lab (opening September 2024) studies the relationship between amino acid metabolism and protein synthesis in cancer cells, seeking to understand how and why amino acid limitation leads to codon-specific ribosome stalling and premature fall-off that inhibits protein production. We employ a variety of genetic and biochemical techniques including fluorescent reporter development, ribosome profiling, charged tRNA-seq, and metabolite/protein mass spectrometry to investigate this direct control of gene expression by amino acid physiology and the tRNA pool.
We are hiring graduate students, research technicians, and postdocs. If you are interested in joining, reach out to Alicia to discuss!
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