Cargando…
Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR‐200 levels in extracellular vesicles
Colorectal cancer (CRC) with a mesenchymal gene expression signature has the greatest propensity for distant metastasis and is characterised by the accumulation of cancer‐associated fibroblasts in the stroma. We investigated whether the epithelial to mesenchymal transition status of CRC cells influe...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122835/ https://www.ncbi.nlm.nih.gov/pubmed/35595718 http://dx.doi.org/10.1002/jev2.12226 |
_version_ | 1784711430089474048 |
---|---|
author | Bhome, Rahul Emaduddin, Muhammad James, Victoria House, Louise M. Thirdborough, Stephen M. Mellone, Massimiliano Tulkens, Joeri Primrose, John N. Thomas, Gareth J. De Wever, Olivier Mirnezami, Alex H. Sayan, A. Emre |
author_facet | Bhome, Rahul Emaduddin, Muhammad James, Victoria House, Louise M. Thirdborough, Stephen M. Mellone, Massimiliano Tulkens, Joeri Primrose, John N. Thomas, Gareth J. De Wever, Olivier Mirnezami, Alex H. Sayan, A. Emre |
author_sort | Bhome, Rahul |
collection | PubMed |
description | Colorectal cancer (CRC) with a mesenchymal gene expression signature has the greatest propensity for distant metastasis and is characterised by the accumulation of cancer‐associated fibroblasts in the stroma. We investigated whether the epithelial to mesenchymal transition status of CRC cells influences fibroblast phenotype, with a focus on the transfer of extracellular vesicles (EVs), as a controlled means of cell–cell communication. Epithelial CRC EVs suppressed TGF‐β‐driven myofibroblast differentiation, whereas mesenchymal CRC EVs did not. This was driven by miR‐200 (miR‐200a/b/c, ‐141), which was enriched in epithelial CRC EVs and transferred to recipient fibroblasts. Ectopic miR‐200 expression or ZEB1 knockdown, in fibroblasts, similarly suppressed myofibroblast differentiation. Supporting these findings, there was a strong negative correlation between miR‐200 and myofibroblastic markers in a cohort of CRC patients in the TCGA dataset. This was replicated in mice, by co‐injecting epithelial or mesenchymal CRC cells with fibroblasts and analysing stromal markers of myofibroblastic phenotype. Fibroblasts from epithelial tumours contained more miR‐200 and expressed less ACTA2 and FN1 than those from mesenchymal tumours. As such, these data provide a new mechanism for the development of fibroblast heterogeneity in CRC, through EV‐mediated transfer of miRNAs, and provide an explanation as to why CRC tumours with greater metastatic potential are CAF rich. |
format | Online Article Text |
id | pubmed-9122835 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91228352022-05-21 Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR‐200 levels in extracellular vesicles Bhome, Rahul Emaduddin, Muhammad James, Victoria House, Louise M. Thirdborough, Stephen M. Mellone, Massimiliano Tulkens, Joeri Primrose, John N. Thomas, Gareth J. De Wever, Olivier Mirnezami, Alex H. Sayan, A. Emre J Extracell Vesicles Research Articles Colorectal cancer (CRC) with a mesenchymal gene expression signature has the greatest propensity for distant metastasis and is characterised by the accumulation of cancer‐associated fibroblasts in the stroma. We investigated whether the epithelial to mesenchymal transition status of CRC cells influences fibroblast phenotype, with a focus on the transfer of extracellular vesicles (EVs), as a controlled means of cell–cell communication. Epithelial CRC EVs suppressed TGF‐β‐driven myofibroblast differentiation, whereas mesenchymal CRC EVs did not. This was driven by miR‐200 (miR‐200a/b/c, ‐141), which was enriched in epithelial CRC EVs and transferred to recipient fibroblasts. Ectopic miR‐200 expression or ZEB1 knockdown, in fibroblasts, similarly suppressed myofibroblast differentiation. Supporting these findings, there was a strong negative correlation between miR‐200 and myofibroblastic markers in a cohort of CRC patients in the TCGA dataset. This was replicated in mice, by co‐injecting epithelial or mesenchymal CRC cells with fibroblasts and analysing stromal markers of myofibroblastic phenotype. Fibroblasts from epithelial tumours contained more miR‐200 and expressed less ACTA2 and FN1 than those from mesenchymal tumours. As such, these data provide a new mechanism for the development of fibroblast heterogeneity in CRC, through EV‐mediated transfer of miRNAs, and provide an explanation as to why CRC tumours with greater metastatic potential are CAF rich. John Wiley and Sons Inc. 2022-05-20 2022-05 /pmc/articles/PMC9122835/ /pubmed/35595718 http://dx.doi.org/10.1002/jev2.12226 Text en © 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Bhome, Rahul Emaduddin, Muhammad James, Victoria House, Louise M. Thirdborough, Stephen M. Mellone, Massimiliano Tulkens, Joeri Primrose, John N. Thomas, Gareth J. De Wever, Olivier Mirnezami, Alex H. Sayan, A. Emre Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR‐200 levels in extracellular vesicles |
title | Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR‐200 levels in extracellular vesicles |
title_full | Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR‐200 levels in extracellular vesicles |
title_fullStr | Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR‐200 levels in extracellular vesicles |
title_full_unstemmed | Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR‐200 levels in extracellular vesicles |
title_short | Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR‐200 levels in extracellular vesicles |
title_sort | epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering mir‐200 levels in extracellular vesicles |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122835/ https://www.ncbi.nlm.nih.gov/pubmed/35595718 http://dx.doi.org/10.1002/jev2.12226 |
work_keys_str_mv | AT bhomerahul epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT emaduddinmuhammad epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT jamesvictoria epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT houselouisem epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT thirdboroughstephenm epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT mellonemassimiliano epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT tulkensjoeri epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT primrosejohnn epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT thomasgarethj epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT deweverolivier epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT mirnezamialexh epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles AT sayanaemre epithelialtomesenchymaltransitioninfluencesfibroblastphenotypeincolorectalcancerbyalteringmir200levelsinextracellularvesicles |