LAUSR

Metastatic bone disease often induces osteolytic lesions caused by an imbalance of osteoblastic bone formation and osteoclastic bone resorption. We could previously show that TAM family receptor tyrosine kinase MERTK exerts an oncogenic function in multiple myeloma, NSCLC and breast cancer bone metastasis, providing a rationale for using MERTK inhibitors in bone metastasis therapy. Furthermore, we reported a thus far unrecognized role of MERTK as a novel negative regulator of osteoblast function and showed that MERTK represents an osteoanabolic target in the tumor microenvironment of bone metastasis by targeting osteoblasts. It is described that MERTK exerts a prominent role in phagocytosis of macrophages. Nevertheless, the role of MERTK in osteoclasts is unknown. To assess a potential role of MERTK in physiological bone remodeling by osteoclasts in vivo, we performed microcomputed tomography (μCT) of tibia of LysM-cre+;Mertkflox/flox mice and observed increased bone volume. Histomorphometry revealed reduced osteoclast number in LysM-cre+;Mertkflox/flox mice, indicating that increased bone volume induced by loss of MERTK in the myeloid lineage is mediated by decreased osteoclast formation in vivo. Interestingly, analysis of TRAP+ mononuclear cells in the metaphyseal bone marrow showed decreased numbers and increased distance to closest bone surface, suggesting dysfunctional osteoclast precursor cell differentiation and migration in LysM-cre+;Mertkflox/flox mice. In vitro assays demonstrated that loss of Mertk results in decreased osteoclast precursor cell migration towards its ligand PROS1 and decreased osteoclast differentiation through a RHOA dependent mechanism. To elucidate if MERTK represents a target in the tumor microenvironment of osteolytic bone metastasis we utilized syngeneic EO771 breast cancer bone metastasis model and injected luciferase transduced EO771 cells into Mertkflox/flox and LysM-cre+;Mertkflox/flox C57BL/6J mice. Metastatic spread was monitored by bioluminescence imaging. Analysis of bone metastasis by μCT showed higher bone volume in EO771 tumor bearing LysM-cre+;Mertkflox/flox mice. Furthermore, osteolysis zones in the cortical bone were markedly decreased. Histomorphometry of TRAP/Hematoxylin staining indicated decreased osteoclast numbers in EO771 tumor bearing LysM-cre+;Mertkflox/flox mice. Furthermore, intratumoral TRAP+ mononuclear cells in breast cancer bone metastases were decreased, indicating that osteolytic bone metastasis recruit osteoclast precursors from its microenvironment in the bone marrow via MERTK to induce osteolysis. In summary, tumor-induced activation of MERTK suppresses and transforms osteoblasts, which counteracts bone formation and recruits osteoclast precursors to form osteoclasts and mediate osteolysis. Hence, MERTK is a novel target in the tumor microenvironment to inhibit osteolytic bone metastasis. Citation Format: Janik Engelmann, Jennifer Zarrer, Kristoffer Riecken, Jonas Waizenegger, Maria Elena Vargas-Delgado, Lara Meier, Carsten Bokemeyer, Klaus Pantel, Emily Alberto, Sourav Ghosh, Carla Rothlin, Eric Hesse, Hanna Taipaleenmäki, Isabel Ben-Batalla, Sonja Loges. MERTK is a target in the microenviroenment of osteolytic bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1189.