Cargando…

Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche

The ability of breast cancer cells to interconvert between epithelial and mesenchymal states contributes to their metastatic potential. As opposed to cell autonomous effects, the impact of epithelial–mesenchymal plasticity (EMP) on primary and metastatic tumor microenvironments remains poorly charac...

Descripción completa

Detalles Bibliográficos
Autores principales: Shinde, Aparna, Paez, Juan Sebastian, Libring, Sarah, Hopkins, Kelsey, Solorio, Luis, Wendt, Michael K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018754/
https://www.ncbi.nlm.nih.gov/pubmed/32054828
http://dx.doi.org/10.1038/s41389-020-0204-5
_version_ 1783497386400677888
author Shinde, Aparna
Paez, Juan Sebastian
Libring, Sarah
Hopkins, Kelsey
Solorio, Luis
Wendt, Michael K.
author_facet Shinde, Aparna
Paez, Juan Sebastian
Libring, Sarah
Hopkins, Kelsey
Solorio, Luis
Wendt, Michael K.
author_sort Shinde, Aparna
collection PubMed
description The ability of breast cancer cells to interconvert between epithelial and mesenchymal states contributes to their metastatic potential. As opposed to cell autonomous effects, the impact of epithelial–mesenchymal plasticity (EMP) on primary and metastatic tumor microenvironments remains poorly characterized. Herein we utilize global gene expression analyses to characterize a metastatic model of EMP as compared to their non-metastatic counterparts. Using this approach, we demonstrate that upregulation of the extracellular matrix crosslinking enzyme tissue transglutaminase-2 (TG2) is part of a novel gene signature that only emerges in metastatic cells that have undergone induction and reversion of epithelial–mesenchymal transition (EMT). Consistent with our model system, patient survival is diminished when primary tumors demonstrate enhanced levels of TG2 in conjunction with its substrate, fibronectin. Targeted depletion of TG2 inhibits metastasis, while overexpression of TG2 is sufficient to enhance this process. In addition to being present within cells, we demonstrate a robust increase in the amount of TG2 and crosslinked fibronectin present within extracellular vesicle (EV) fractions derived from metastatic breast cancer cells. Confocal microscopy of these EVs suggests that FN undergoes fibrillogenesis on their surface via a TG2 and Tensin1-dependent process. Upon in vivo administration, the ability of tumor-derived EVs to induce metastatic niche formation and enhance subsequent pulmonary tumor growth requires the presence and activity of TG2. Finally, we develop a novel 3D model of the metastatic niche to demonstrate that conditioning of pulmonary fibroblasts via pretreatment with tumor-derived EVs promotes subsequent growth of breast cancer cells in a TG2-dependent fashion. Overall, our studies illustrate a novel mechanism through which EMP contributes to metastatic niche development and distant metastasis via tumor-derived EVs containing aberrant levels of TG2 and fibrillar FN.
format Online
Article
Text
id pubmed-7018754
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-70187542020-03-03 Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche Shinde, Aparna Paez, Juan Sebastian Libring, Sarah Hopkins, Kelsey Solorio, Luis Wendt, Michael K. Oncogenesis Article The ability of breast cancer cells to interconvert between epithelial and mesenchymal states contributes to their metastatic potential. As opposed to cell autonomous effects, the impact of epithelial–mesenchymal plasticity (EMP) on primary and metastatic tumor microenvironments remains poorly characterized. Herein we utilize global gene expression analyses to characterize a metastatic model of EMP as compared to their non-metastatic counterparts. Using this approach, we demonstrate that upregulation of the extracellular matrix crosslinking enzyme tissue transglutaminase-2 (TG2) is part of a novel gene signature that only emerges in metastatic cells that have undergone induction and reversion of epithelial–mesenchymal transition (EMT). Consistent with our model system, patient survival is diminished when primary tumors demonstrate enhanced levels of TG2 in conjunction with its substrate, fibronectin. Targeted depletion of TG2 inhibits metastasis, while overexpression of TG2 is sufficient to enhance this process. In addition to being present within cells, we demonstrate a robust increase in the amount of TG2 and crosslinked fibronectin present within extracellular vesicle (EV) fractions derived from metastatic breast cancer cells. Confocal microscopy of these EVs suggests that FN undergoes fibrillogenesis on their surface via a TG2 and Tensin1-dependent process. Upon in vivo administration, the ability of tumor-derived EVs to induce metastatic niche formation and enhance subsequent pulmonary tumor growth requires the presence and activity of TG2. Finally, we develop a novel 3D model of the metastatic niche to demonstrate that conditioning of pulmonary fibroblasts via pretreatment with tumor-derived EVs promotes subsequent growth of breast cancer cells in a TG2-dependent fashion. Overall, our studies illustrate a novel mechanism through which EMP contributes to metastatic niche development and distant metastasis via tumor-derived EVs containing aberrant levels of TG2 and fibrillar FN. Nature Publishing Group UK 2020-02-13 /pmc/articles/PMC7018754/ /pubmed/32054828 http://dx.doi.org/10.1038/s41389-020-0204-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Shinde, Aparna
Paez, Juan Sebastian
Libring, Sarah
Hopkins, Kelsey
Solorio, Luis
Wendt, Michael K.
Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
title Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
title_full Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
title_fullStr Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
title_full_unstemmed Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
title_short Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
title_sort transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018754/
https://www.ncbi.nlm.nih.gov/pubmed/32054828
http://dx.doi.org/10.1038/s41389-020-0204-5
work_keys_str_mv AT shindeaparna transglutaminase2facilitatesextracellularvesiclemediatedestablishmentofthemetastaticniche
AT paezjuansebastian transglutaminase2facilitatesextracellularvesiclemediatedestablishmentofthemetastaticniche
AT libringsarah transglutaminase2facilitatesextracellularvesiclemediatedestablishmentofthemetastaticniche
AT hopkinskelsey transglutaminase2facilitatesextracellularvesiclemediatedestablishmentofthemetastaticniche
AT solorioluis transglutaminase2facilitatesextracellularvesiclemediatedestablishmentofthemetastaticniche
AT wendtmichaelk transglutaminase2facilitatesextracellularvesiclemediatedestablishmentofthemetastaticniche