Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, and Jonathan L Coloff. 2023. “
ASCT2 is the primary serine transporter in cancer cells.” bioRxiv.
AbstractThe non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic for serine and therefore reliant on the uptake of exogenous serine. Importantly, however, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (coded for by the gene SLC1A5) as the primary serine transporter in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target in serine metabolism.
Christopher Chidley, Alicia M. Darnell, Benjamin L. Gaudio, Evan C. Lien, Anna M. Barbeau, Matthew G. Vander Heiden, and Peter K. Sorger. 2023. “
A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.” bioRxiv.
Publisher's VersionAbstractBlocking 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 CRISPRi/a screening platform to systematically interrogate the contribution of specific nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumor models. We applied this platform to identify the transporters of amino acids in leukemia cells and found that amino acid transport is characterized by high bidirectional flux that is dependent on the composition of the microenvironment. While investigating the role of transporters in cystine starved cells, we uncovered a novel role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumors and found that levels of glucose and amino acids can restrain proliferation in that environment. This study provides a framework for the systematic identification of critical cellular nutrient transporters, characterizing the function of such transporters, and studying how the tumor microenvironment impacts cancer metabolism.Competing Interest StatementM.G.V.H. is a scientific advisor for Agios Pharmaceuticals, iTeos Therapeutics, Sage Therapeutics, Auron Therapeutics, and Droia Ventures. P.K.S. is a co-founder and member of the BOD of Glencoe Software, a member of the BOD of Applied Biomath, and a member of the SAB of RareCyte, NanoString and Montai Health, and a consultant for Merck. P.K.S. declares that none of these relationships have influenced the content of this manuscript. The other authors declare no competing interests.