Tumour-derived extracellular vesicles containing microRNA-125b as activators of cancer-associated fibroblasts in breast cancer

Research output: Conference Papers (RGC: 31A, 31B, 32, 33)Posterpeer-review

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Author(s)

  • Victor Ma
  • Camille A. Mathey-Andrews
  • Chun Kuen Lam
  • Theodoros Kiomourtzis
  • Jingmin Jin
  • Larry McReynolds
  • Andrew Grimson
  • William C. Cho
  • Judy Lieberman

Detail(s)

Original languageEnglish
Publication statusPublished - 2 Aug 2019

Conference

TitleThe First Joint Conference on Extracellular Vesicles in Cancer
LocationVanderbilt University
PlaceUnited States
City Nashville
Period2 - 4 August 2019

Abstract

Introduction: Metastasis, as the leading cause of cancer-associated deaths in breast cancer, is a complex process which depends on the interactions in the tumour microenvironment (TME) between tumour cells and stromal cells including fibroblasts. Tumour cells are known to secret extracellular vesicles (EVs) in great abundance which contain functional biomolecules such as microRNAs to modulate the TME. These exciting findings from previous studies inspired us to investigate the TME modulation mediated by tumour-derived EVs.

Methods: We generated both mouse and human breast cancer cell lines that secret fluorescent EVs for tracing purposes and identified the subtypes of recipient cells that actively take up tumour-derived EVs in mouse models using flow cytometry. RNA sequencing was used to identify the microRNA cargo in mouse breast cancer cell lines and their EVs. A series of in vitro assays and in vivo experiments confirmed the uptake of microRNA-125b by fibroblasts via tumour-derived EVs and demonstrated its subsequent effects on the activation of cancer-associated fibroblasts (CAFs).

Results: Fibroblasts are the major recipient cells of tumour-derived EVs either in primary tumours or at lung metastatic sites. Highly metastatic mouse breast cancer 4T1 and isogenic, weakly metastatic 4TO7 cells robustly secret miR-125b into their EVs as profiled by RNA sequencing. In mouse tumour models, coinjection with 4T1 EVs resulted in an elevated activation of CAFs in 4TO7 tumours as compared to coinjection with PBS control, which could be rescued by functional blocking of microRNA-125b in 4T1 EVs. Consistent with findings in mouse cells, human metastatic breast cancer cells secret microRNA-125b into EVs and the uptake of such EVs induced an increased level of microRNA-125b in fibroblasts and thus CAFs activation denoted by expression of related markers. Similar to knockdown of established microRNA-125b targets, an activated phenotype was achieved by overexpression of microRNA-125b in both mouse and human fibroblasts.

Conclusions: Tumour-derived EVs act as avid vehicles to transport microRNA-125b from breast cancer cells to resident fibroblasts in the TME which leads to their activation into CAFs.

Bibliographic Note

Full text of this publication does not contain sufficient affiliation information. With consent from the author(s) concerned, the Research Unit(s) information for this record is based on the existing academic department affiliation of the author(s).

Citation Format(s)

Tumour-derived extracellular vesicles containing microRNA-125b as activators of cancer-associated fibroblasts in breast cancer. / Vu, Tien Luyen; Peng, Boya; Zhang, Daniel Xin; Ma, Victor; Mathey-Andrews, Camille A.; Lam, Chun Kuen; Kiomourtzis, Theodoros ; Jin, Jingmin; McReynolds, Larry; Huang, Linfeng; Grimson, Andrew; Cho, William C.; Lieberman, Judy; Le, Minh Tn.

2019. Poster session presented at The First Joint Conference on Extracellular Vesicles in Cancer, Nashville, United States.

Research output: Conference Papers (RGC: 31A, 31B, 32, 33)Posterpeer-review