The impact of myostatin on breast cancer and multiple myeloma bone metastases

• Applicant: Berno Dankbar, Ph.D.
• Subject Area: Hematology, Oncology
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401133176

The growth of cancers in the skeleton is associated with severe effects on bone and results in considerable morbidity and mortality. Both, breast cancer (BC) as well as multiple multiple (MM)-derived bone metastases are osteolytic and generation of metastases is mediated by the formation and activation of mature osteoclasts.There is a complex crosstalk between tumor cells and the bone microenvironment providing a variety of growth factors for cancer cells and osteoclastic factors. In this regard inhibition of TGFß or activin A, both members of the TGFß familiy, suppress osteoclastic bone resorption in mouse models of MM and BC, indicating an important role of these factors in the formation of bone metastases.In this context, we have recently discovered that myostatin, another member of the TGFß family, strongly enhances osteoclast development and that deficiency or inhibition of myostatin highly ameliorates disease severity and in particular bone erosion in arthritic mice. Interestingly, preliminary experiments revealed a high similarity between mystatin and action A. We could show that myostatin and activin A enhance RANKL-induced osteoclast formation to the same extent, indicating that both factors are equivalent promoters of osteoclast development. Moreover, both factors act via similar Smad-pathways (Smad2/3), pointing to a common mechanism in osteoclast differentiation. Beside this similarity, additional lines of evidence suggest a role for myostatin in bone metastases: 1. Myostatin is expressed in breast cancer cells, 2. ActRII, the receptor type shared by activin and myostatin, is expressed by breast cancer and myeloma cells, 3. Higher levels of phosphorylated SMAD2 are present in human BC bone metastatases.We hypothesize, that myostatin participates in the interactions of tumor cells with the bone microenvironment, promoting osteoclast development and thereby bone lesions and that inhibition of myostatin reduce bone metastases.For this purpose, we will treat two syngeneic and two xenograft models for both BC and MM with anti-myostatin antibody and assess the formation of bone metastases. Moreover, the role of myostatin in cell-cell interaction will be investigated and direct/ indirect effects of tumor cells on osteoclast differentiation and activity will be tested. Furthermore, assuming that both myostatin and activin A are involved in bone metastases, inhibiting myostatin and activin A simultaneously may provide a powerful tool for the treatment of bone metastases in BC and MM. A protein which is able to bind and antagonize myostatin as well as activin is a natural occuring antagonist called „Follistatin-related gene“ (FLRG). In preliminary experiments, we could demonstrate that FLRG completely abrogates RANKL-induced osteoclast formation either stimulated with myostatin and activin. We therefore proposed to treat BC and MM mice also with recombinant FLRG in the course of the disease and analysed as described above.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2084: µBONE: Colonization and interaction of tumor cells within the bone microenvironment
• Co-Investigator: Professor Dr. Thomas Pap