Osteoblasts as novel target to treat breast cancer bone metastases

• Applicant: Professorin Dr. Hanna Taipaleenmäki, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277691607

Bone is the predominant site for breast cancer metastases, which often cause a non-curable condition with osteolytic lesions and muscle weakness. Given the osteolytic nature of breast cancer bone metastases, osteoclast activation is considered the cellular hallmark of the disease. However, in the course of the Emmy Noether program we demonstrated that metastatic bone disease also depends on osteoblasts. Briefly, we established osteoblasts as novel regulators of bone metastases and revealed that osteoblast-targeting therapies alleviate bone metastatic burden. Furthermore, we identified a novel anti-microRNA (anti-miR)-based approach to simultaneously reduce tumor growth and to enhance osteoblast function. Interestingly, while investigating the role of osteoblasts in bone metastases, we identified a novel osteoblast-derived cell population that is located inside metastases, possibly supporting tumor growth. Using in vitro techniques, in vivo approaches and patient samples we have shown that cancer cells stimulate osteoblast migration and alter cell morphology from cuboidal to a spindle-like shape. Based on these findings we hypothesize that osteoblasts acquire a cancer-associated fibroblast (CAF)-like phenotype upon contact with cancer cells. To test this hypothesis, we propose to investigate the molecular signature of this novel osteoblast-derived cancer-associated cell population using lineage-tracing and single cell sequencing. In addition, we aim to elucidate the function of these cells to provide new avenues to develop a CAF-targeting therapy to treat bone metastases. Patients with metastatic breast cancer often suffer from muscle weakness. Interestingly, we discovered that anti-miR-19a/b treatment not only reduces metastatic burden but also protects from cancer-induced loss of muscle function. Our preliminary results suggest that anti-miR-19a/b prevents pathologically increased autophagy in myoblasts. Thus, we propose to use cell- and molecular biology approaches to test the hypothesis that anti-miR-19a/b restores cancer-induced autophagy by targeting Bim. If true, inhibition of miR-19a/b may constitute an innovative therapeutic approach to target the musculoskeletal system. The experiments outlined in this grant application are expected to i) provide translationally relevant insights into the function of cells of the osteoblast lineage in the metastatic bone environment, and ii) reveal the mechanisms by which anti-miR-19a/b regulates cancer-induced muscle weakness. Since no curative approach is available to restore the health of the musculoskeletal system in patients with bone metastases, these studies are original and innovative and likely to provide a significant contribution to the field of musculoskeletal oncology.

• DFG Programme: Independent Junior Research Groups