Attenuating bone metastases by inhibiting Ror2 signaling and osteoblast senescence

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Bone metastases are a frequent and devastating late-stage event in patients with advanced breast cancer. In the bone microenvironment, breast cancer cells disturb physiological bone remodeling by stimulating osteoclast-mediated bone resorption and suppressing osteoblast-mediated bone formation, leading to an osteolytic disease. Although anti-resorptive treatments are efficient to attenuate bone destruction, osteolytic lesions remain with the disease being incurable. Recent studies by our group and others demonstrate that affecting bone remodeling in a therapeutic manner reduces breast cancer homing to bone and metastatic growth in the bone microenvironment. Furthermore, pharmacological augmentation of bone formation protects from breast cancer-induced bone destruction, an unsuspected finding of great translational value. To continue this novel and innovative line of research during the second funding period of this priority program, we aim to identify unprecedented bone anabolic cues to alleviate bone metastatic burden, thereby reducing pathological bone destruction. In this context, we made the interesting observation that non-canonical Wnt signaling, inhibits bone formation. Using a comprehensive set of in vivo and in vitro approaches we uncovered that receptor of tyrosine kinase-like orphan receptor 2 (Ror2) diminishes osteoblast differentiation and bone formation. Mechanistically, Ror2-deficiency in osteoblasts impairs interleukin 6 (IL-6) signaling, which is a negative regulator of osteoblast differentiation, a key cytokine mediating the pathological cellular crosstalk in bone metastases and an important component of the senescence-associated secretory phenotype (SASP). Interestingly, while breast cancer stimulates osteoblasts to adopt a SASP, Ror2-deficient osteoblasts are resistant to develop an oxidative stress-induced SASP. These findings let us to hypothesize that inhibition of Ror2 signaling and consequently osteoblast senescence might attenuate breast cancer-induced bone destruction. To address this hypothesis, we propose to i) determine the role of Ror2 in osteoblasts in breast cancer bone metastases, ii) investigate breast cancer cell-induced Ror2-mediated osteoblast senescence, and iii) reduce Ror2 signaling and senescence to alleviate metastatic bone disease. Experimentally, we will use novel oligonucleotide-based gene silencing approaches combined with state-of-the-art mouse genetics, metastases models and the latest technology of bone imaging and quality testing. Mechanistic insights will be elucidated using cell- and molecular biology approaches and clinical relevance of the findings will be ensured by implementing patient samples in our investigations. This project is original and expected to expand the knowledge on non-canonical Wnt signaling in bone pathology and may reveal novel targets for the development of potential future interventions to treat patients with breast cancer-induced bone disease.