Abstract 296P
Background
The 5-year survival rates for metastatic breast cancer are stuck at <30%. The plateauing of progress suggests the need for improved, dynamic, 3D, and human models of this multi-tissue process. Breast cancer metastasis also tends to have a subtype dependent organotropism. Here we show that using a novel organs-on-a-chip platform we have been able to recapitulate the multiple stages of both multi-tissue and tissue-specific breast cancer metastasis for the first time in an entirely human in vitro model.
Methods
Our approach involved generating bioengineered human bone, lung, and endothelial tissues from primary cells. These were subsequently co-cultured in our microfluidic multi-organs-on-a-chip platform, and exposed to metastatic breast cancer cell lines injected into and circulating within it. GFP-luciferase tagged triple-negative breast cancer cells, and their subclones that have previously been isolated from mice and shown to consistently target either bone or lung tissues in vivo, were used, and their spread to the tissues was monitored over 2 weeks. Tissue specific functions were assessed throughout the process of metastatic progression using a combination of assays, and compared against clinical benchmarks.
Results
We found that the use of an organs-on-a-chip platform with a vascular barrier was critical to both the maintenance of tissue specific function and to the recapitulation of breast cancer metastasis across both tissues. Additionally, we were able to recreate metastasis-specific processes documented in breast cancer patients, including the multiple stages of the metastatic cascade and osteolytic cycle activation. Finally, we were able to use our fully human and bioengineered integrated multi-tissue model in combination with organ-specific breast cancer subclones to recreate targeted bone and lung metastases.
Conclusions
Breast cancer metastasis is a complicated, dynamic, and clinically important process of cancer that requires new models to enable more impactful study. Our model system offers a variety of advantages: it is entirely human, yet manages to incorporate multiple tissue types, recreate multiple stages of metastatic progression, and capture the organ-specificity of various breast cancer subclones.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Cancer Institute (USA).
Disclosure
All authors have declared no conflicts of interest.