Reactivation of Prostate Cancer Proliferation from Dormancy by Osteoclastic Tunneling Nanotubes

Prostate cancer (PCa) cells have an exceptional ability to survive in bone marrow, where disseminated tumor cells (DTCs) can remain dormant for years. Despite advances, the precise mechanisms by which DTCs escape dormancy and form skeletal metastases remain elusive. Osteoclasts (OCs) contribute to tumor growth via a "vicious cycle," releasing growth factors from the bone matrix that stimulate cancer proliferation. However, current OC-targeted therapies fail to completely prevent metastatic progression. This suggests alternative mechanisms are at play. We propose that osteoclastic tunneling nanotubes (TNTs) are key mediators in activating dormant DTC (dDTC) proliferation. TNTs are membranous conduits facilitating intercellular transfer of molecules and signals. Our preliminary data suggest contact between OCs and DTCs via TNTs reactivates cellular proliferation. The central hypothesis is that dDTCs are driven into the cell cycle by osteoclasts using tunneling nanotubes which may constitute innovative therapeutic targets. Our 1st Aim focuses on discerning the cellular mechanisms of dDTC reactivation via TNTs, specifically assessing how TNT regulation affects dDTC proliferation and identifying critical molecular signals transferred in this process using an MS-SILAC approach. Our 2nd Aim will validate these TNT interactions in a metastatic dormancy model using immunocompetent mice, to explore their significance in bone marrow reactivation and tumor relapse. Our animal models are critical in this process because they recapitulate key features of the bone metastatic microenvironment, tumor dormancy, immune and stromal interactions, and disease progression that cannot be fully modeled in vitro. Identifying and targeting pathways involved in dDTC reactivation could lead to new therapies specifically preventing bone metastasis, improving patient quality of life and survival. The phased research strategy—from identifying facilitators of proliferation to validating proteins in an animal model of tumor dormancy and metastasis ensures thorough investigation and translation to clinical applications. By elucidating the role of TNTs in PCa dormancy, we aim to uncover transformative therapeutic opportunities. Project Number: 1R21CA312961-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: RUSSELL TAICHMAN | Institution: TUFTS UNIVERSITY BOSTON, BOSTON, MA | Award Amount: $433,759 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BTC-F (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11356470