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

doi:10.1016/j.isci.2022.104193

EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer

iScience. 2022 Apr 1;25(5):104193. doi: 10.1016/j.isci.2022.104193. eCollection 2022 May 20.

Authors

Debasis Nayak¹, Brenna Weadick¹, Avinash K Persaud¹, Radhika Raj¹, Reena Shakya², Junan Li³, Moray J Campbell^{4

5}, Rajgopal Govindarajan^{1

6}

Affiliations

¹ Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USA.
² Target Validation Shared Resource, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
³ The Ohio State University College of Pharmacy, Columbus, OH 43210, USA.
⁴ Molecular Carcinogenesis and Chemoprevention Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
⁵ Biomedical Informatics Shared Resource, The Ohio State University, Columbus, OH 43210, USA.
⁶ Translational Therapeutics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.

Abstract

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.

Keywords: Biological sciences; Cancer; Immunology.

Abstract

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