MicroRNAs (miRNAs) appear to play a role in mediating interactions between cancer cells and their hosting niche during cancer progression and metastasis. Our preliminary studies indicate that miR-105, whose levels in the circulation are associated with metastatic progression in early-stage breast cancer (BC) patients, is characteristically expressed and secreted by metastatic BC (MBC) cells. MiR-105 downregulates the tight junction protein ZO-1, for which reduced expression is associated with metastasis in BC patients. MiR-105 potently induces migration and proliferation in MBC cells, and can be transferred via MBC-secreted exosomes to normal epithelial and endothelial cells in the cancer niche, where it alters ZO-1 expression and the barrier function of these niche cells. In a mouse model established in our lab, MBC-secreted exosomes and miRNAs can be internalized by cells in various tissues, and can facilitate metastasis development. The goals of this study are to dissect the dual roles of miR-105 in regulating the metastatic potential of cancer cells and in destroying the epithelial and endothelial """"""""barriers"""""""" in the cancer niche, and t explore novel therapeutic strategies that target miR-105-mediated pro-metastatic functions.
In Aim 1, the effects of miR-105 on cancer cell adhesion, migration, invasion, proliferation and anchorage-independent growth, as well as the role of ZO-1 in mediating these effects, will be investigated. Additional miR-105-regulated genes will be identified and their role in mediating miR-105's effects will be determined.
In Aim 2, the effects of cancer-secreted, exosome-transferred miR-105 on normal epithelial and endothelial niche cells will be determined, focusing on their """"""""barrier"""""""" functions to restrict cancer cell invasion and metastasis. The magnitude and kinetics of miR-105-mediated barrier-destroying effects will be determined by co-culturing the epithelial and endothelial niche cells with MBC cells that secrete miR-105.
In Aim 3, the in vivo effects of miR-105 on niche adaptation and BC metastasis will be determined using mouse xenograft models of BC. The anti-metastatic effect of miR- 105 intervention will be evaluated. These in-depth functional studies of cancer-secreted miRNAs that contribute to the co-evolution of the tumor-hosting environment will provide novel insights into the dynamic communication between cancer and host during disease progression. This study will also provide proof-of- principle for targeting cancer-secreted miRNAs as a novel approach to block the cancer-directed, pro-metastatic remodeling of the niche at early cancer stages for the prevention of metastasis. Our long-term objectives are to validate the miR-105 pathway in primary BC and establish standard approaches to identify patients suitable for therapies that target miR-105, to understand the global effects of cancer-secreted miRNAs, and to elucidate cancer-secreted, circulating miRNAs (e.g., miR-105) in BC patients as blood-borne markers for early diagnosis or prediction of metastasis.

Public Health Relevance

Metastasis, the leading cause of mortality in cancer patients, is a multi-event process that involves interplay between cancer cells and the cancer-hosting niche. Our previous studies suggest that miR-105, a microRNA characteristically produced and secreted by metastatic breast cancer cells, can be transferred from cancer to the niche, and disrupt the anti-cancer """"""""barriers"""""""" in the normal niche to promote metastasis. In the proposed study, we will dissect the dual role of miR-105 in regulating the potential of cancer cells to spread and in adapting the cancer niche, and will explore novel therapeutic strategies that target miR-105 to block this unique communication between cancer and host, and ultimately, to prevent metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
City of Hope/Beckman Research Institute
United States
Zip Code
Yan, Wei; Wu, Xiwei; Zhou, Weiying et al. (2018) Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol 20:597-609
Chin, Andrew R; Yan, Wei; Cao, Minghui et al. (2018) Polarized Secretion of Extracellular Vesicles by Mammary Epithelia. J Mammary Gland Biol Neoplasia 23:165-176
Chin, Andrew R; Wang, Shizhen Emily (2016) Cancer-derived extracellular vesicles: the 'soil conditioner' in breast cancer metastasis? Cancer Metastasis Rev 35:669-676
Chin, Andrew R; Wang, Shizhen Emily (2016) Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications. Clin Cancer Res 22:3725-33
Chin, Andrew R; Fong, Miranda Y; Somlo, George et al. (2016) Cross-kingdom inhibition of breast cancer growth by plant miR159. Cell Res 26:217-28
Fong, Miranda Y; Zhou, Weiying; Liu, Liang et al. (2015) Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17:183-94
Chow, Amy; Zhou, Weiying; Liu, Liang et al. (2014) Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-?B. Sci Rep 4:5750
Liu, Liang; Zhou, Weiying; Cheng, Chun-Ting et al. (2014) TGF? induces ""BRCAness"" and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes. Mol Cancer Res 12:1597-609
Zhou, Weiying; Fong, Miranda Y; Min, Yongfen et al. (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25:501-15