EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer
Debasis Nayak,
Brenna Weadick,
Avinash K. Persaud,
Radhika Raj,
Reena Shakya,
Junan Li,
Moray J. Campbell,
Rajgopal Govindarajan
Affiliations
Debasis Nayak
Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USA
Brenna Weadick
Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USA
Avinash K. Persaud
Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USA
Radhika Raj
Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USA
Reena Shakya
Target Validation Shared Resource, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
Junan Li
The Ohio State University College of Pharmacy, Columbus, OH 43210, USA
Moray J. Campbell
Molecular Carcinogenesis and Chemoprevention Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Biomedical Informatics Shared Resource, The Ohio State University, Columbus, OH 43210, USA
Rajgopal Govindarajan
Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USA; Translational Therapeutics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; Corresponding author
Summary: The involvement of membrane-bound solute carriers (SLCs) in neoplastic transdifferentiation processes is poorly defined. Here, we examined changes in the SLC landscape during epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. We show that two SLCs from the organic anion/cation transporter family, SLC22A10 and SLC22A15, favor EMT via interferon (IFN) α and γ signaling activation of receptor tyrosine kinase-like orphan receptor 1 (ROR1) expression. In addition, SLC22A10 and SLC22A15 allow tumor cell accumulation of glutathione to support EMT via the IFNα/γ-ROR1 axis. Moreover, a pan-SLC22A inhibitor lesinurad reduces EMT-induced metastasis and gemcitabine chemoresistance to prolong survival in mouse models of pancreatic cancer, thus identifying new vulnerabilities for human PDAC.
