EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer
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/cat...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-05-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222004631 |
| _version_ | 1818551995629305856 |
|---|---|
| author | Debasis Nayak Brenna Weadick Avinash K. Persaud Radhika Raj Reena Shakya Junan Li Moray J. Campbell Rajgopal Govindarajan |
| author_facet | Debasis Nayak Brenna Weadick Avinash K. Persaud Radhika Raj Reena Shakya Junan Li Moray J. Campbell Rajgopal Govindarajan |
| author_sort | Debasis Nayak |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T09:07:19Z |
| format | Article |
| id | doaj.art-7f4a4a2d3e4b42b5a8bce96353c443e8 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-12T09:07:19Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-7f4a4a2d3e4b42b5a8bce96353c443e82022-12-22T00:29:37ZengElsevieriScience2589-00422022-05-01255104193EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancerDebasis Nayak0Brenna Weadick1Avinash K. Persaud2Radhika Raj3Reena Shakya4Junan Li5Moray J. Campbell6Rajgopal Govindarajan7Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, OH 43210, USATarget Validation Shared Resource, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USAThe Ohio State University College of Pharmacy, Columbus, OH 43210, USAMolecular 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, USADivision 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222004631Biological sciencesImmunologyCancer |
| spellingShingle | Debasis Nayak Brenna Weadick Avinash K. Persaud Radhika Raj Reena Shakya Junan Li Moray J. Campbell Rajgopal Govindarajan EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer iScience Biological sciences Immunology Cancer |
| title | EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer |
| title_full | EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer |
| title_fullStr | EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer |
| title_full_unstemmed | EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer |
| title_short | EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer |
| title_sort | emt alterations in the solute carrier landscape uncover slc22a10 a15 imposed vulnerabilities in pancreatic cancer |
| topic | Biological sciences Immunology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222004631 |
| work_keys_str_mv | AT debasisnayak emtalterationsinthesolutecarrierlandscapeuncoverslc22a10a15imposedvulnerabilitiesinpancreaticcancer AT brennaweadick emtalterationsinthesolutecarrierlandscapeuncoverslc22a10a15imposedvulnerabilitiesinpancreaticcancer AT avinashkpersaud emtalterationsinthesolutecarrierlandscapeuncoverslc22a10a15imposedvulnerabilitiesinpancreaticcancer AT radhikaraj emtalterationsinthesolutecarrierlandscapeuncoverslc22a10a15imposedvulnerabilitiesinpancreaticcancer AT reenashakya emtalterationsinthesolutecarrierlandscapeuncoverslc22a10a15imposedvulnerabilitiesinpancreaticcancer AT junanli emtalterationsinthesolutecarrierlandscapeuncoverslc22a10a15imposedvulnerabilitiesinpancreaticcancer AT morayjcampbell emtalterationsinthesolutecarrierlandscapeuncoverslc22a10a15imposedvulnerabilitiesinpancreaticcancer AT rajgopalgovindarajan emtalterationsinthesolutecarrierlandscapeuncoverslc22a10a15imposedvulnerabilitiesinpancreaticcancer |