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Cancer cells educate natural killer cells to a metastasis-promoting cell state

Natural killer (NK) cells have potent antitumor and antimetastatic activity. It is incompletely understood how cancer cells escape NK cell surveillance. Using ex vivo and in vivo models of metastasis, we establish that keratin-14(+) breast cancer cells are vulnerable to NK cells. We then discovered...

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Autores principales: Chan, Isaac S., Knútsdóttir, Hildur, Ramakrishnan, Gayathri, Padmanaban, Veena, Warrier, Manisha, Ramirez, Juan Carlos, Dunworth, Matthew, Zhang, Hao, Jaffee, Elizabeth M., Bader, Joel S., Ewald, Andrew Josef
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480097/
https://www.ncbi.nlm.nih.gov/pubmed/32645139
http://dx.doi.org/10.1083/jcb.202001134
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author Chan, Isaac S.
Knútsdóttir, Hildur
Ramakrishnan, Gayathri
Padmanaban, Veena
Warrier, Manisha
Ramirez, Juan Carlos
Dunworth, Matthew
Zhang, Hao
Jaffee, Elizabeth M.
Bader, Joel S.
Ewald, Andrew Josef
author_facet Chan, Isaac S.
Knútsdóttir, Hildur
Ramakrishnan, Gayathri
Padmanaban, Veena
Warrier, Manisha
Ramirez, Juan Carlos
Dunworth, Matthew
Zhang, Hao
Jaffee, Elizabeth M.
Bader, Joel S.
Ewald, Andrew Josef
author_sort Chan, Isaac S.
collection PubMed
description Natural killer (NK) cells have potent antitumor and antimetastatic activity. It is incompletely understood how cancer cells escape NK cell surveillance. Using ex vivo and in vivo models of metastasis, we establish that keratin-14(+) breast cancer cells are vulnerable to NK cells. We then discovered that exposure to cancer cells causes NK cells to lose their cytotoxic ability and promote metastatic outgrowth. Gene expression comparisons revealed that healthy NK cells have an active NK cell molecular phenotype, whereas tumor-exposed (teNK) cells resemble resting NK cells. Receptor–ligand analysis between teNK cells and tumor cells revealed multiple potential targets. We next showed that treatment with antibodies targeting TIGIT, antibodies targeting KLRG1, or small-molecule inhibitors of DNA methyltransferases (DMNT) each reduced colony formation. Combinations of DNMT inhibitors with anti-TIGIT or anti-KLRG1 antibodies further reduced metastatic potential. We propose that NK-directed therapies targeting these pathways would be effective in the adjuvant setting to prevent metastatic recurrence.
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spelling pubmed-74800972021-03-07 Cancer cells educate natural killer cells to a metastasis-promoting cell state Chan, Isaac S. Knútsdóttir, Hildur Ramakrishnan, Gayathri Padmanaban, Veena Warrier, Manisha Ramirez, Juan Carlos Dunworth, Matthew Zhang, Hao Jaffee, Elizabeth M. Bader, Joel S. Ewald, Andrew Josef J Cell Biol Report Natural killer (NK) cells have potent antitumor and antimetastatic activity. It is incompletely understood how cancer cells escape NK cell surveillance. Using ex vivo and in vivo models of metastasis, we establish that keratin-14(+) breast cancer cells are vulnerable to NK cells. We then discovered that exposure to cancer cells causes NK cells to lose their cytotoxic ability and promote metastatic outgrowth. Gene expression comparisons revealed that healthy NK cells have an active NK cell molecular phenotype, whereas tumor-exposed (teNK) cells resemble resting NK cells. Receptor–ligand analysis between teNK cells and tumor cells revealed multiple potential targets. We next showed that treatment with antibodies targeting TIGIT, antibodies targeting KLRG1, or small-molecule inhibitors of DNA methyltransferases (DMNT) each reduced colony formation. Combinations of DNMT inhibitors with anti-TIGIT or anti-KLRG1 antibodies further reduced metastatic potential. We propose that NK-directed therapies targeting these pathways would be effective in the adjuvant setting to prevent metastatic recurrence. Rockefeller University Press 2020-07-09 /pmc/articles/PMC7480097/ /pubmed/32645139 http://dx.doi.org/10.1083/jcb.202001134 Text en © 2020 Chan et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Report
Chan, Isaac S.
Knútsdóttir, Hildur
Ramakrishnan, Gayathri
Padmanaban, Veena
Warrier, Manisha
Ramirez, Juan Carlos
Dunworth, Matthew
Zhang, Hao
Jaffee, Elizabeth M.
Bader, Joel S.
Ewald, Andrew Josef
Cancer cells educate natural killer cells to a metastasis-promoting cell state
title Cancer cells educate natural killer cells to a metastasis-promoting cell state
title_full Cancer cells educate natural killer cells to a metastasis-promoting cell state
title_fullStr Cancer cells educate natural killer cells to a metastasis-promoting cell state
title_full_unstemmed Cancer cells educate natural killer cells to a metastasis-promoting cell state
title_short Cancer cells educate natural killer cells to a metastasis-promoting cell state
title_sort cancer cells educate natural killer cells to a metastasis-promoting cell state
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480097/
https://www.ncbi.nlm.nih.gov/pubmed/32645139
http://dx.doi.org/10.1083/jcb.202001134
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