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, JoyceSlingerland, and Andy J. Minn

 Cell. 2014 Oct 23;159(3):499-513.

Speaker: Yin-Ping Wang (王尹平)                                       Time: 14:10~15:00, May. 13, 2015

Commentator: Dr. Chun Hei Cheung (張雋曦 教授)          Place: Room 601

Abstract:

Stromal cells play an important role in cancer development. Interaction between stromal cells and cancer cells has an influence on therapeutic resistance (1). In the previous study, interferon-related DNA damage resistance signature (IRDS), the major genes of which were identified as interferon-stimulated genes (ISGs), were discovered to be associated with radiation (RT) and chemotherapy (chemo) resistance (2). This study aims to investigate how stromal cells interact with breast cancer cells to regulate ISGs expression and therapy resistance. Coculture of breast cancer cells and stromal cells mediates IRDS induction and RT/chemo resistance, while monoculture does not. For the upregulation of genes in ISGs activation, RIG-I, a pattern recognition receptor (PRR), is determined to be the most influential factor. It is reported that PRRs can be activated by exosomes, which are secreted vesicles that enable cell communication(3). Further investigation reveals that this RIG-I antiviral signaling is activated by the exosomes containing 5’-triphosphate RNA, which are transferred from the stromal. Meanwhile, stromal cells cause NOTCH3 activation on breast cancer cells, and JAG1, a membrane-bound ligand of NOTCH3, is induced in both breast cancer and stromal cells. NOTCH3 is a cell membrane receptor activated by binding to its ligands and plays a role in drug resistance. The RIG-I antiviral paracrine and NOTCH3 juxtacrine pathways converge as STAT1, which triggers the transcription of NOTCH3 target genes as well as the expansion of therapy-resistant tumor-initiating cells. In summary, this study demonstrates that breast cancer cells can communicate with stromal cells to initiate antiviral/NOTCH3 pathways, resulting in stroma-mediated resistance.

References:

1.  Mao, Y., Keller, E.T., Garfield, D.H., Shen, K., and Wang, J. (2013). Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32, 303-315.

2.     Weichselbaum, R.R., Ishwaran, H., Yoon, T., Nuyten, D.S., Baker, S.W., Khodarev, N., Su, A.W., Shaikh, A.Y., Roach, P., Kreike, B., et al. (2008). An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci U S A 105, 18490-18495.

3.     Thery, C., Ostrowski, M., and Segura, E. (2009). Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9, 581-593.