Project Summary
For breast cancer, skeletal metastases are a major source of the pain, disability and mortality associated with
disease progression. As with other solid tumors metastasizing to bone, breast cancer displays a striking tropism
for vertebral bone, with approximately 2-5 vertebral metastases for every one long bone metastasis, implying
that vertebral-specific factors are key drivers of metastasis. Passive blood flow cannot explain the increased
metastatic tropism for vertebral versus long bones, indicating that unrecognized biologic factors are likely to drive
the high rates of vertebral metastasis observed clinically.
We have here identified a new skeletal stem cell responsible for generating the osteoblasts that
mineralize and remodel the vertebrae (vertebral skeletal stem cells, vSSCs) and provide evidence that this cell
is a major determinant of vertebral-specific pathology, including the high rates of vertebral metastases observed
clinically. Even after normalizing all anatomic factors through the use of in vivo bone organoids, vSSC-derived
bone tissue recruited tumor cells more efficiently than comparable stem cells from long bones. Targeting loss-
of-function to vSSCs using a mouse cre line developed for this project selectively reduces vertebral metastasis
rates. In both organoid systems and native vertebrae, vSSCs drive high rates of initial vertebral seeding with
tumor cells, indicating that vSSC-driven tropism is a major contributing factor behind the high vertebral metastatic
rates observed in breast cancer. Building upon this observation, we have identified candidate trophic factors
expressed by vSSCs and have generated evidence implicating specific vSSC-derived factors in vertebral
metastatic tropism and outgrowth.
Here, we will perform key studies needed to advance the rigor, underlying mechanism, clinical relevance
and translational therapeutic impact of this discovery. First, (Aim 1), we will establish the metastatic functions of
this vSSC in the native vertebral environment, including investigating how vSSCs may organize the entire
vertebral metastatic niche and which vSSC-derived cell types contribute to metastasis. Next (Aim 2), we have
identified a candidate vSSC-derived mediator driving metastatic tropism and will here determine how secretion
of this factor is regulated and how it signals to tumor cells to impact metastasis. Lastly (Aim 3), we will develop
the therapeutic impact of this discovery by determining if the human counterparts of vSSCs display a conserved
metastatic function in xenograft systems and by conducting proof-of-concept therapeutic studies of blocking
candidate vSSC-derived metastatic mediators. Altogether, this study will establish that a new stem cell
responsible for forming the vertebrae drives vertebral metastases, thereby offering a new model for the site
specificity of skeletal metastases, an explanation for the high rates of vertebral metastases observed clinically
and new therapeutic opportunities.