For women in the U.S., breast cancer ranks second in the frequency of cancer diagnoses (first is skin cancer), and second as the cause of death due to cancer (first is lung cancer). Overall five-year survival rates now approach 90%, and have increased steadily since the mid 1970s (~ 70%). However, approximately 20% of women with breast cancer will suffer a recurrence, a third of the time occurring >10 years after initial treatment. The most common site of breast cancer metastasis is the bone, and, importantly, at the time of the initial diagnosis approximately 40% of women with breast cancer already have microscopic disseminated tumor cells (DTC) in the bone marrow. Importantly, bone marrow DTCs have a low proliferation rate, many markers of cancer stem cells, and are resistant to current therapies. The presence of DTCs is associated with worsened survival and a higher incidence of relapse. This project proposes to combine microfluidic and tissue engineering technology to create a 3D in vitro model of human bone marrow that includes perfused human capillaries.
The specific aims are to: 1) Develop a 3D in vitro model of bone marrow stroma that includes both the vascular niche and the endosteal niche; and 2) Perform the preliminary characterization of breast cancer cell extravasation in an inflammatory bone marrow microenvironment. The in vitro model can uniquely simulate and visualize the dynamic steps of breast cancer extravasation and dormancy with extremely high temporal and spatial resolution. Completing the specific aims will provide a new and novel model of human bone marrow, and position our team to pursue impactful mechanistic questions regarding breast cancer metastasis and dormancy through competitive extramural funding.
This proposal will develop a novel 3D in vitro model of human bone marrow comprised of perfused human microvessels, bone marrow stromal cells, and bone-forming cells (osteoblasts). The model will be used to characterize the relationship between systemic inflammation, extravasation, and dormancy in breast cancer. The results may lead to new therapeutic options to target dormant breast cancer cells in the bone marrow.
