Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways

Mirjam C. Boelens, Tony J. Wu, Barzin Y. Nabet, Bihui Xu, Yu Qiu, Taewon Yoon, Diana J. Azzam, Christina Twyman-Saint Victor, Brianne Z. Wiemann, Hemant Ishwaran, Petra J. Ter Brugge, Jos Jonkers, Joyce M Slingerland, Andy J. Minn

Research output: Contribution to journalArticle

332 Citations (Scopus)

Abstract

Stromal communication with cancer cells can influence treatment response. We show that stromal and breast cancer (BrCa) cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance. Upon heterotypic interaction, exosomes are transferred from stromal to BrCa cells. RNA within exosomes, which are largely noncoding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I to activate STAT1-dependent antiviral signaling. In parallel, stromal cells also activate NOTCH3 on BrCa cells. The paracrine antiviral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy-resistant tumor-initiating cells. Primary human and/or mouse BrCa analysis support the role of antiviral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance, which is abrogated by combination therapy with gamma secretase inhibitors. Thus, stromal cells orchestrate an intricate crosstalk with BrCa cells by utilizing exosomes to instigate antiviral signaling. This expands BrCa subpopulations adept at resisting therapy and reinitiating tumor growth.

Original languageEnglish
Pages (from-to)499-513
Number of pages15
JournalCell
Volume159
Issue number3
DOIs
StatePublished - Oct 23 2014

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Exosomes
Cell- and Tissue-Based Therapy
Antiviral Agents
Cells
Breast Neoplasms
Tumors
Stromal Cells
Pattern Recognition Receptors
Amyloid Precursor Protein Secretases
DNA Transposable Elements
Chemotherapy
Exosome Multienzyme Ribonuclease Complex
Crosstalk
Paracrine Communication
Neoplastic Stem Cells
RNA
Therapeutics
Radiation
Neoplasms
Communication

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Boelens, M. C., Wu, T. J., Nabet, B. Y., Xu, B., Qiu, Y., Yoon, T., ... Minn, A. J. (2014). Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell, 159(3), 499-513. https://doi.org/10.1016/j.cell.2014.09.051

Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. / Boelens, Mirjam C.; Wu, Tony J.; Nabet, Barzin Y.; Xu, Bihui; Qiu, Yu; Yoon, Taewon; Azzam, Diana J.; Twyman-Saint Victor, Christina; Wiemann, Brianne Z.; Ishwaran, Hemant; Ter Brugge, Petra J.; Jonkers, Jos; Slingerland, Joyce M; Minn, Andy J.

In: Cell, Vol. 159, No. 3, 23.10.2014, p. 499-513.

Research output: Contribution to journalArticle

Boelens, MC, Wu, TJ, Nabet, BY, Xu, B, Qiu, Y, Yoon, T, Azzam, DJ, Twyman-Saint Victor, C, Wiemann, BZ, Ishwaran, H, Ter Brugge, PJ, Jonkers, J, Slingerland, JM & Minn, AJ 2014, 'Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways', Cell, vol. 159, no. 3, pp. 499-513. https://doi.org/10.1016/j.cell.2014.09.051
Boelens, Mirjam C. ; Wu, Tony J. ; Nabet, Barzin Y. ; Xu, Bihui ; Qiu, Yu ; Yoon, Taewon ; Azzam, Diana J. ; Twyman-Saint Victor, Christina ; Wiemann, Brianne Z. ; Ishwaran, Hemant ; Ter Brugge, Petra J. ; Jonkers, Jos ; Slingerland, Joyce M ; Minn, Andy J. / Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. In: Cell. 2014 ; Vol. 159, No. 3. pp. 499-513.
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