Dissecting the role of TAM receptor-ligand interactions in mediating homing and bone colonization by bone seeking cancers

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The TAM family of receptor tyrosine kinases, consisting of TYRO3 (BRT, DTK, RSE, SKY and TIF), AXL (ARK, TYRO7 and UFO) and MERTK (EYK, NYM and TYRO12) and their cognate ligands growth-arrest-specific gene-6 (GAS6) and protein S (PROS1) are aberrantly expressed in a wide variety of cancer entities and promote oncogenesis.Bone-seeking tumors including multiple myeloma, lung- and breast cancer express GAS6 and PROS1 and it was shown that the GAS6-TYRO3 axis induces osteoclast (OC) differentiation. Consistently, germline deletion of TYRO3 leads to increased bone mass. However, nothing is known about the cell type-specific functions of TAMR in bone cells and the function of PROS1 in cancers metastasizing to the bone. Therefore, during the first funding period of Bone we investigated the role of PROS1 and TAMR in bone homeostasis and studied the therapeutic potential of the small molecule MERTK inhibitor R992.Our most important discovery is that treatment of bone-seeking myeloma-, breast- and lung cancer mouse models with R992 exerted a potent osteoanabolic effect by counteracting cancer-induced osteopenia and normalizing bone homeostasis. Mechanistically, this was achieved by a direct and specific stimulation of osteoblast (OB) differentiation via blockade of the PROS1-MERTK-RhoA-ROCK axis. Altogether, the targeting of MERTK opens up new avenues for the treatment of bone seeking cancers and their associated morbidities due to osteopenia/osteolysis. Based on our findings, we will dissect the roles of PROS1, GAS6 and TAMR in metastatic bone colonization by breast and prostate cancer. We hypothesize that TAMR ligands, which are highly expressed by osteoprogenitor cells (OPC) and OB, attract tumor cells to the endosteal niche. In addition, we will study the impact of MERTK blockade on the bone microenvironment at the single cell level including effects on important immune cell populations eliciting anti-tumor immune responses in the bone marrow. For potential clinical translation we will develop and preclinically validate anti-human MERTK function blocking antibodies for potential use in humans to treat bone seeking cancers and cancer-induced osteopenia. If successful we will seek additional funding for a clinical trial after the next funding period of Bone. Altogether, we will substantially increase the knowledge about the TAMR-guided homing of cancers commonly metastasizing to bone and develop a therapeutic antibody targeting this process.