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Published on: May 19, 2011
A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments
Christopher Chidley1, Alicia M Darnell2, Benjamin L Gaudio3
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA. christopher_chidley@hms.harvard.edu.
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.
Insights
Targeting nutrient transporters is key for cancer therapy. This study developed a screening platform to identify essential transporters in leukemia and tumors, revealing microenvironment-dependent nutrient flux and novel roles in preventing cell death.
Area of Science:
- Cancer Biology
- Molecular Biology
- Metabolic Pathways
Background:
- Targeting nutrient import is a promising cancer therapy strategy.
- Identifying specific nutrient transporters crucial for cancer cell survival and proliferation is challenging.
- The tumor microenvironment significantly influences cancer cell metabolism and transporter function.
Purpose of the Study:
- To develop and apply a CRISPR screening platform for systematically identifying essential nutrient transporters in cancer.
- To characterize the role of amino acid transporters in leukemia cells and their dependence on microenvironment.
- To uncover novel nutrient transporter functions, including those involved in ferroptosis and tumor growth.
Main Methods:
- CRISPR interference/activation screening platform to interrogate nutrient transporter function.
- Application of the platform to leukemia cells and subcutaneous tumor models.
- Analysis of nutrient flux, cell proliferation, and ferroptosis under varying environmental conditions.
Main Results:
- Identified critical amino acid transporters in leukemia, demonstrating high bidirectional flux influenced by microenvironment.
- Discovered a role for serotonin uptake in preventing ferroptosis in cystine-starved cells.
- Found that glucose and amino acid availability can limit proliferation in subcutaneous tumors, identifying essential transporters for tumor growth.
Conclusions:
- Established a robust framework for systematic identification and functional characterization of cellular nutrient transporters.
- Highlighted the dynamic and microenvironment-dependent nature of nutrient transport in cancer.
- Provided insights into novel therapeutic targets and strategies for modulating cancer metabolism.
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