文章基本信息

标题：EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer
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作者：Debasis Nayak ; Brenna Weadick ; Avinash K. Persaud 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：5
页码：1-33
DOI：10.1016/j.isci.2022.104193
语种：English
出版社：Elsevier
摘要：SummaryThe 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.Graphical abstractDisplay OmittedHighlights•Comprehensive transportome analysis identifies key SLC alterations during PDAC EMT•SLC22A10 and SLC22A15 trigger IFN signaling to promote PDAC aggressiveness•SLC22A10 and SLC22A15 facilitate glutathione accumulation to promote IFN signaling•Lesinurad impeded the SLC22A10/15 adverse effects in PDAC mouse modelsBiological sciences; Immunology; Cancer