The integrated mechanobiology and glycobiology of bone metastasis

Breast cancer is the most common cancer in women and frequently metastasizes to the skeleton, leading to poor prognosis. As existing therapies are relatively ineffective, a promising strategy could be to eradicate dormant tumor cells before they become activated. Indeed, tumor cells disseminate to the skeleton early during disease where they can remain quiescent for years or decades. Better understanding the mechanisms that regulate the fate of disseminated tumor cells prior to lesion formation promises to inform therapeutic options to prevent metastasis. Upon arrival in bone, tumor cells colonize osteogenic niches where they interact with mineralizing bone matrix and are protected from immune attack by Natural Killer (NK) and T cells. Although decreased bone mineral density is a known risk factor for bone metastasis, it remains elusive how varied bone mineral density affects early stages of the metastatic cascade including immune evasion. Defining these links is critical as bone matrix is a dynamic biomaterial whose physicochemical properties regulate the behavior of many cell types and, thus, is likely to also influence disseminated tumor cells and their interactions with the immunological microenvironment. Our preliminary data suggest that physiological bone mineral content inhibits tumor cell growth while increasing latency due to metabolic and mechanosignaling reprogramming. In addition, we recently identified that bone mineral content-dependent metabolic programs direct tumor-cell synthesis of immunomodulatory “glyco-codes” that favor immune evasion. Based on these promising preliminary data, we have assembled a multidisciplinary team of experts in tumor engineering and bone metastasis, mechano- and glycobiology, and transcriptomic approaches to study the overall hypothesis that the mineral content of bone matrix influences early-stage metastasis by enriching for less proliferative, stem-like tumor cells that are immuno-privileged and can drive metastatic outgrowth when bone mineral content is perturbed. To address this hypothesis, we will combine innovative in vitro, in vivo, and bioinformatic approaches with advanced imaging to test how variations in bone mineral content regulate tumor cell mechanosignaling and metabolism and how these changes impact the proliferative and dormant phenotype of tumor cells in the skeleton. In parallel, we will elucidate how changes in bone mineral content instruct tumor-cell synthesis of an immunomodulatory glycocalyx using our unique tools for glycocalyx materials research which include genetic methods to engineer the structure of the glycocalyx, computational models to understand the physical behaviors of the glycocalyx at biointerfaces, and optical tools to characterize the glycocalyx structure. This powerful combination of innovative conceptual advances and technologies will enable us to define how changes in bone mineral content regulate skeletal metastasis and link these changes to targetable cellular mechanisms.