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Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells
Mutated forms of the RAS oncogene drive 30% of all cancers, but they cannot be targeted therapeutically using currently available drugs. The molecular and cellular mechanisms that create a heterogenous tumor environment harboring both mutant and wild-type RAS have not been elucidated. In this study,...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678395/ https://www.ncbi.nlm.nih.gov/pubmed/31247990 http://dx.doi.org/10.3390/cancers11070892 |
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author | Desir, Snider Wong, Phillip Turbyville, Thomas Chen, De Shetty, Mihir Clark, Christopher Zhai, Edward Romin, Yevgeniy Manova-Todorova, Katia Starr, Timothy K. Nissley, Dwight V. Steer, Clifford J. Subramanian, Subbaya Lou, Emil |
author_facet | Desir, Snider Wong, Phillip Turbyville, Thomas Chen, De Shetty, Mihir Clark, Christopher Zhai, Edward Romin, Yevgeniy Manova-Todorova, Katia Starr, Timothy K. Nissley, Dwight V. Steer, Clifford J. Subramanian, Subbaya Lou, Emil |
author_sort | Desir, Snider |
collection | PubMed |
description | Mutated forms of the RAS oncogene drive 30% of all cancers, but they cannot be targeted therapeutically using currently available drugs. The molecular and cellular mechanisms that create a heterogenous tumor environment harboring both mutant and wild-type RAS have not been elucidated. In this study, we examined horizontal transfer of mutant KRAS between colorectal cancer (CRC) cells via a direct form of cell-to-cell communication called tunneling nanotubes (TNTs). TNT formation was significantly higher in CRC cell lines expressing mutant KRAS than CRC cell lines expressing wild-type RAS; this effect was most pronounced in metastatic CRC cell lines with both mutant KRAS and deficiency in mismatch repair proteins. Using inverted and confocal fluorescence time-lapse and fluorescence recovery after photobleaching (FRAP)-based microscopy, we observed GFP-tagged mutant KRAS(G12D) protein trafficking between CRC cells through TNTs within a span of seconds to several minutes. Notably, acquisition of mutant KRAS increased Extracellular Signal-regulated Kinase (ERK) phosphorylation and upregulated tunneling nanotube formation in recipient wildtype CRC cells. In conclusion, these findings suggest that intercellular horizontal transfer of RAS can occur by TNTs. We propose that intercellular transfer of mutant RAS can potentially induce intratumoral heterogeneity and result in a more invasive phenotype in recipient cells. |
format | Online Article Text |
id | pubmed-6678395 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66783952019-08-19 Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells Desir, Snider Wong, Phillip Turbyville, Thomas Chen, De Shetty, Mihir Clark, Christopher Zhai, Edward Romin, Yevgeniy Manova-Todorova, Katia Starr, Timothy K. Nissley, Dwight V. Steer, Clifford J. Subramanian, Subbaya Lou, Emil Cancers (Basel) Article Mutated forms of the RAS oncogene drive 30% of all cancers, but they cannot be targeted therapeutically using currently available drugs. The molecular and cellular mechanisms that create a heterogenous tumor environment harboring both mutant and wild-type RAS have not been elucidated. In this study, we examined horizontal transfer of mutant KRAS between colorectal cancer (CRC) cells via a direct form of cell-to-cell communication called tunneling nanotubes (TNTs). TNT formation was significantly higher in CRC cell lines expressing mutant KRAS than CRC cell lines expressing wild-type RAS; this effect was most pronounced in metastatic CRC cell lines with both mutant KRAS and deficiency in mismatch repair proteins. Using inverted and confocal fluorescence time-lapse and fluorescence recovery after photobleaching (FRAP)-based microscopy, we observed GFP-tagged mutant KRAS(G12D) protein trafficking between CRC cells through TNTs within a span of seconds to several minutes. Notably, acquisition of mutant KRAS increased Extracellular Signal-regulated Kinase (ERK) phosphorylation and upregulated tunneling nanotube formation in recipient wildtype CRC cells. In conclusion, these findings suggest that intercellular horizontal transfer of RAS can occur by TNTs. We propose that intercellular transfer of mutant RAS can potentially induce intratumoral heterogeneity and result in a more invasive phenotype in recipient cells. MDPI 2019-06-26 /pmc/articles/PMC6678395/ /pubmed/31247990 http://dx.doi.org/10.3390/cancers11070892 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Desir, Snider Wong, Phillip Turbyville, Thomas Chen, De Shetty, Mihir Clark, Christopher Zhai, Edward Romin, Yevgeniy Manova-Todorova, Katia Starr, Timothy K. Nissley, Dwight V. Steer, Clifford J. Subramanian, Subbaya Lou, Emil Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells |
title | Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells |
title_full | Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells |
title_fullStr | Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells |
title_full_unstemmed | Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells |
title_short | Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells |
title_sort | intercellular transfer of oncogenic kras via tunneling nanotubes introduces intracellular mutational heterogeneity in colon cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678395/ https://www.ncbi.nlm.nih.gov/pubmed/31247990 http://dx.doi.org/10.3390/cancers11070892 |
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