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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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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. |
format | Online Article Text |
id | pubmed-7480097 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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