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Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR-200 levels in extracellular vesicles

Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR-200 levels in extracellular vesicles
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 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.
2001-3078
Bhome, Rahul
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Emaduddin, Muhammad
1c4f1035-e6f8-44e9-89c5-5ccb4ef72d1b
Mellone, Massimiliano
b0301b32-14f8-4203-9026-b7f90885cab9
Thirdborough, Stephen
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Primrose, John
d85f3b28-24c6-475f-955b-ec457a3f9185
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Mirnezami, Alexander
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Sayan, Abdulkadir Emre
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077
Bhome, Rahul
d7b1e0d3-5925-460a-871d-5f52f69c649b
Emaduddin, Muhammad
1c4f1035-e6f8-44e9-89c5-5ccb4ef72d1b
Mellone, Massimiliano
b0301b32-14f8-4203-9026-b7f90885cab9
Thirdborough, Stephen
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Primrose, John
d85f3b28-24c6-475f-955b-ec457a3f9185
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Mirnezami, Alexander
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Sayan, Abdulkadir Emre
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077

Bhome, Rahul, Emaduddin, Muhammad, Mellone, Massimiliano, Thirdborough, Stephen, Primrose, John, Thomas, Gareth, Mirnezami, Alexander and Sayan, Abdulkadir Emre (2022) Epithelial to mesenchymal transition influences fibroblast phenotype in colorectal cancer by altering miR-200 levels in extracellular vesicles. Journal of Extracellular Vesicles, 11 (5).

Record type: Article

Abstract

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.

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Accepted/In Press date: 26 April 2022
Published date: 20 May 2022

Identifiers

Local EPrints ID: 457215
URI: http://eprints.soton.ac.uk/id/eprint/457215
ISSN: 2001-3078
PURE UUID: 6454639e-c9dd-43ec-b8db-57b9f5461917
ORCID for Massimiliano Mellone: ORCID iD orcid.org/0000-0002-4964-9340
ORCID for John Primrose: ORCID iD orcid.org/0000-0002-2069-7605
ORCID for Abdulkadir Emre Sayan: ORCID iD orcid.org/0000-0002-5291-1485

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Date deposited: 26 May 2022 16:50
Last modified: 24 Jul 2022 01:43

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Contributors

Author: Rahul Bhome
Author: Muhammad Emaduddin
Author: Massimiliano Mellone ORCID iD
Author: John Primrose ORCID iD
Author: Gareth Thomas

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