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Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins
While there have been tremendous efforts to target oncogenic RAS signaling from inside the cell, little effort has focused on the cell-surface. Here, we used quantitative surface proteomics to reveal a signature of proteins that are upregulated on cells transformed with KRAS(G12V), and driven by MAP...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796798/ https://www.ncbi.nlm.nih.gov/pubmed/29359686 http://dx.doi.org/10.7554/eLife.31098 |
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author | Martinko, Alexander J Truillet, Charles Julien, Olivier Diaz, Juan E Horlbeck, Max A Whiteley, Gordon Blonder, Josip Weissman, Jonathan S Bandyopadhyay, Sourav Evans, Michael J Wells, James A |
author_facet | Martinko, Alexander J Truillet, Charles Julien, Olivier Diaz, Juan E Horlbeck, Max A Whiteley, Gordon Blonder, Josip Weissman, Jonathan S Bandyopadhyay, Sourav Evans, Michael J Wells, James A |
author_sort | Martinko, Alexander J |
collection | PubMed |
description | While there have been tremendous efforts to target oncogenic RAS signaling from inside the cell, little effort has focused on the cell-surface. Here, we used quantitative surface proteomics to reveal a signature of proteins that are upregulated on cells transformed with KRAS(G12V), and driven by MAPK pathway signaling. We next generated a toolkit of recombinant antibodies to seven of these RAS-induced proteins. We found that five of these proteins are broadly distributed on cancer cell lines harboring RAS mutations. In parallel, a cell-surface CRISPRi screen identified integrin and Wnt signaling proteins as critical to RAS-transformed cells. We show that antibodies targeting CDCP1, a protein common to our proteomics and CRISPRi datasets, can be leveraged to deliver cytotoxic and immunotherapeutic payloads to RAS-transformed cancer cells and report for RAS signaling status in vivo. Taken together, this work presents a technological platform for attacking RAS from outside the cell. |
format | Online Article Text |
id | pubmed-5796798 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-57967982018-02-05 Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins Martinko, Alexander J Truillet, Charles Julien, Olivier Diaz, Juan E Horlbeck, Max A Whiteley, Gordon Blonder, Josip Weissman, Jonathan S Bandyopadhyay, Sourav Evans, Michael J Wells, James A eLife Biochemistry and Chemical Biology While there have been tremendous efforts to target oncogenic RAS signaling from inside the cell, little effort has focused on the cell-surface. Here, we used quantitative surface proteomics to reveal a signature of proteins that are upregulated on cells transformed with KRAS(G12V), and driven by MAPK pathway signaling. We next generated a toolkit of recombinant antibodies to seven of these RAS-induced proteins. We found that five of these proteins are broadly distributed on cancer cell lines harboring RAS mutations. In parallel, a cell-surface CRISPRi screen identified integrin and Wnt signaling proteins as critical to RAS-transformed cells. We show that antibodies targeting CDCP1, a protein common to our proteomics and CRISPRi datasets, can be leveraged to deliver cytotoxic and immunotherapeutic payloads to RAS-transformed cancer cells and report for RAS signaling status in vivo. Taken together, this work presents a technological platform for attacking RAS from outside the cell. eLife Sciences Publications, Ltd 2018-01-23 /pmc/articles/PMC5796798/ /pubmed/29359686 http://dx.doi.org/10.7554/eLife.31098 Text en © 2018, Martinko et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Martinko, Alexander J Truillet, Charles Julien, Olivier Diaz, Juan E Horlbeck, Max A Whiteley, Gordon Blonder, Josip Weissman, Jonathan S Bandyopadhyay, Sourav Evans, Michael J Wells, James A Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins |
title | Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins |
title_full | Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins |
title_fullStr | Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins |
title_full_unstemmed | Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins |
title_short | Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins |
title_sort | targeting ras-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796798/ https://www.ncbi.nlm.nih.gov/pubmed/29359686 http://dx.doi.org/10.7554/eLife.31098 |
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