A microphysiological model of prostate cancer metastasis into vascularized and innervated bone

About This Grant

SUMMARY Prostate cancer exhibits evident predilection for bone metastasis, occurring in over 80% of advanced cases and causing serious skeletal complications. While organ-on-a-chip platforms have advanced metastasis research, existing microphysiologic bone metastasis models fail to recapitulate critical microenvironmental features, particularly functional vascular networks, innervation and controlled nanoscale mineralization around cells, all which govern metastatic colonization. Building on the seed (tumor cells) and soil (metastatic microenvironment) paradigm of cancer metastasis, we developed an innovative bone metastasis-on-a-chip platform incorporating a mineralized, osteocyte-embedded bone matrix supporting active osteoclast/osteoblast remodeling, perfusable pericyte-supported vasculature to study extravasation dynamics, and integrated neural networks to promote tumor-nerve crosstalk. Our preliminary data reveal that circulating tumor cells (CTCs) experience mechanical nuclear deformation during bone vascular transit, a distinctive phenomenon of metastasis that is absent in other vascular models, suggesting that bone-specific vascular forces may prime metastatic adaptation. Simultaneously, we discovered that neural components actively upregulate pro-metastatic molecular profiles in tumor cells while undergoing tumor-induced remodeling. Here, in Aim 1, we will leverage this platform to interpret how bone-specific vascular mechanics, including pericyte-stabilized endothelial interactions and cellular deformation, orchestrate CTC extravasation and subsequent osteolytic destruction, combining high-resolution live imaging with single- cell analyses of deformation-induced genomic/epigenetic changes. In Aim 2, we will elucidate neural contributions to metastatic niche formation, testing how bidirectional tumor-nerve signaling accelerates bone colonization and bone resorption/destruction. This work addresses two understudied yet pivotal aspects of the metastatic cascade: the deformation and genomic instability of CTC fate during vascular transit, and the neural contribution to of the "vicious cycle" of prostate cancer metastasis into bone. By integrating vascular, neural, and osseous components into a single physiologically relevant, all human platform, we will establish the first model capable of emulating the tripartite interplay driving prostate cancer's bone tropism. The resulting insights and tools will not only reveal new therapeutic targets for bone metastasis but also provide a high-fidelity platform for studying microenvironmental regulation of metastasis across cancer types.