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

由TYRO3 (BRT， DTK， RSE， SKY和TIF), AXL （ARK， TYRO7和UFO）和MERTK （EYK， NYM和TYRO12）及其同源配体生长抑制特异性基因6 （GAS6）和蛋白S （PROS1）组成的受体酪氨酸激酶TAM家族在多种癌症实体中异常表达并促进肿瘤发生。包括多发性骨髓瘤、肺癌和乳腺癌在内的寻骨肿瘤表达GAS6和PROS1， GAS6- tyro3轴诱导破骨细胞（OC）分化。一致地，种系缺失TYRO3导致骨量增加。然而，TAMR在骨细胞中的细胞类型特异性功能以及PROS1在癌症转移到骨中的功能尚不清楚。因此，在Bone的第一个资助期内，我们研究了PROS1和TAMR在骨稳态中的作用，并研究了小分子MERTK抑制剂R992的治疗潜力。我们最重要的发现是，用R992治疗骨髓瘤、乳腺癌和肺癌小鼠模型，通过对抗癌症引起的骨质减少和使骨稳态正常化，发挥了强有力的骨合成代谢作用。从机制上讲，这是通过阻断pro1 - mertk - rhoa - rock轴直接特异性刺激成骨细胞（OB）分化实现的。总之，靶向MERTK为治疗骨癌及其因骨质减少/骨溶解引起的相关发病率开辟了新的途径。基于我们的研究结果，我们将分析PROS1， GAS6和TAMR在乳腺癌和前列腺癌转移性骨定植中的作用。我们推测，由骨祖细胞（OPC）和OB高度表达的TAMR配体将肿瘤细胞吸引到内皮生态位。此外，我们将在单细胞水平上研究MERTK阻断对骨微环境的影响，包括对骨髓中引发抗肿瘤免疫反应的重要免疫细胞群的影响。为了潜在的临床转化，我们将开发和临床前验证抗人MERTK功能阻断抗体，用于治疗人类寻求骨的癌症和癌症引起的骨质减少。如果成功，我们将在Bone的下一个资助期后寻求额外的临床试验资金。总之，我们将大大增加对tamr引导的通常转移到骨的癌症归巢的了解，并开发针对这一过程的治疗性抗体。

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.