This Faculty Early Career Development (CAREER) award will determine how specialized force-sensing bone cells (osteocytes) are impaired by bone metastatic breast cancer, and how this impairment leads to tumor-induced bone disease. The skeleton is a common site for breast cancer metastasis, which causes bone loss, fragility, and ultimately fractures. However, current therapies do not address bone health. Mechanical signals, which occur during daily physical activity, are well-known to improve to bone health, and they may also be protective against tumor-induced bone disease. The working hypothesis of this award is that osteocytes are the key to a better scientific understanding of the causes and treatments of tumor-induced bone disease. Specifically, this work will evaluate if bone metastatic breast cancer causes a dysfunctional osteocyte response to mechanical signals, which causes bone loss. The results from this project will expand basic knowledge about the role of both mechanical cues and osteocytes in metastatic cancer. This award also exemplifies interdisciplinary research. The Educational Objective is to train a diverse Science, Technology, Engineering, and Mathematics workforce. Undergraduate researchers from under-represented groups will gain and leverage research skills critical to Science, Technology, Engineering, and Mathematics careers through formalized training. This training will include targeted professional development and team-based interdisciplinary projects, which will expand career possibilities for engineers in under-represented groups.
To test the working hypothesis, this award will examine the impacts of: 1) breast cancer bone metastasis on bone remodeling mechanisms that are osteocyte-directed and mechanically-regulated, 2) mechanical loading applied to breast cancer cells on the mechanoresponse of osteocytes, and 3) breast cancer subtype on osteocyte mechanoresponse. This research capitalizes on the innovative in vitro/in vivo experimental approaches pioneered by the Principal Investigator. In vivo, controlled mechanical loading will be applied to mouse models of breast cancer bone metastasis. In vitro, osteocytes will be cultured in 3-dimensions and subjected to multiple mechanical cues (fluid flow and matrix deformation) – an advancement over the most commonly used 2-dimension-flow only platforms. In aggregate, results from this research will transform current understanding of bone metastasis by establishing that bone metastatic tumor cells interfere with the mechanoresponse of osteocytes, which is a new mechanism contributing to tumor-induced bone disease and fragility.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
