Investigating the role of FKBP10 in prostate cancer bone metastasis through osteo-mimicry and the collagen crosslinking axis

Prostate cancer (PCa) is a leading cause of cancer-related mortality in men, with nearly 90% of patients with advanced disease developing bone metastases. PCa bone metastasis (PCaBM) represents a major clinical challenge and is associated with severe pain, pathologic fractures, and treatment-resistance. Understanding the molecular mechanisms driving early colonization is critical to identifying novel therapeutic targets and improving patient outcomes. We hypothesized that FK506-binding protein 10 (FKBP10), an ER-chaperone integral to collagen maturation, promotes PCaBM by reprogramming cancer cells to adopt bone-like characteristics, a process termed osteo-mimicry. Our data demonstrate that FKBP10 expression correlates with bone-metastatic PCa tissue and, when silenced, affects (1) osteogenic pathways, including those involved in Type 1 collagen maturation and skeletal development, and (2) PCa cells’ proliferative, migratory, and invasive properties. Given FKBP10’s established role in collagen maturation in bone cells, we investigated whether it functions similarly in PCa cells; FKBP10-overexpression was found to enhance its interactions with LH2 and enrichment with COL1A1, supporting its involvement in the collagen crosslinking axis. Additionally, this is the first study to show osteogenic induction to increase FKBP10 expression at mRNA and protein levels in PCa cells. Under these conditions, we also observed FKBP10-overexpression to upregulate mRNA expression of osteo-mimetic genes SPARC, WNT5A, and BMP7. However, several alternative osteo-mimetic genes remained unchanged or undetectable at baseline conditions. As a result, while these findings linked FKBP10 to the collagen crosslinking axis in PCa, additional studies are required to establish whether it promotes osteo-mimicry through the regulation of osteo-mimetic genes. Investigations attaining a global understanding of the effects of FKBP10 on osteogenic genes at both the mRNA and protein level, and their bidirectional relationship, will be essential in determining whether FKBP10 functions as a regulator, downstream effector, or component of osteo-mimetic reprogramming. Elucidating the effects of FKBP10-LH2 interactions on secreted collagen and the extracellular matrix will also be critical in understanding the therapeutic potential of FKBP10. This study offers a novel approach with the potential to shift the treatment paradigm for bone metastasis patients by providing strategies to disrupt early metastatic events, significantly reducing the clinical burden and pain associated with PCaBM.