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

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 trans...

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Autores principales: Nayak, Debasis, Weadick, Brenna, Persaud, Avinash K., Raj, Radhika, Shakya, Reena, Li, Junan, Campbell, Moray J., Govindarajan, Rajgopal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036131/
https://www.ncbi.nlm.nih.gov/pubmed/35479410
http://dx.doi.org/10.1016/j.isci.2022.104193
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author Nayak, Debasis
Weadick, Brenna
Persaud, Avinash K.
Raj, Radhika
Shakya, Reena
Li, Junan
Campbell, Moray J.
Govindarajan, Rajgopal
author_facet Nayak, Debasis
Weadick, Brenna
Persaud, Avinash K.
Raj, Radhika
Shakya, Reena
Li, Junan
Campbell, Moray J.
Govindarajan, Rajgopal
author_sort Nayak, Debasis
collection PubMed
description 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.
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spelling pubmed-90361312022-04-26 EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer Nayak, Debasis Weadick, Brenna Persaud, Avinash K. Raj, Radhika Shakya, Reena Li, Junan Campbell, Moray J. Govindarajan, Rajgopal iScience Article 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. Elsevier 2022-04-01 /pmc/articles/PMC9036131/ /pubmed/35479410 http://dx.doi.org/10.1016/j.isci.2022.104193 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Nayak, Debasis
Weadick, Brenna
Persaud, Avinash K.
Raj, Radhika
Shakya, Reena
Li, Junan
Campbell, Moray J.
Govindarajan, Rajgopal
EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic 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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036131/
https://www.ncbi.nlm.nih.gov/pubmed/35479410
http://dx.doi.org/10.1016/j.isci.2022.104193
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