Dissecting the role of TAM receptors in myeloma-induced osteoclast activation and their immune-modulatory function

多发性骨髓瘤(MM)的一个特点是PC和破骨细胞(OC)之间的恶性相互作用。这种串扰会导致疾病进展、免疫抑制和溶骨性骨病。尽管多发性骨髓瘤的治疗取得了重大进展，但在大多数患者中，这种疾病仍然是无法治愈的。因此，发现促进骨髓瘤及其相关骨病的新机制仍是迫切需要的。在这种背景下，发展对骨髓瘤细胞、免疫细胞和骨细胞之间相互作用的了解是特别有意义的，因为免疫细胞具有摧毁恶性细胞的巨大潜力。然而，骨髓中抗骨髓瘤免疫反应的调节和治疗激活尚不清楚。我们的初步数据表明，蛋白S(Pros)促进了MM细胞的增殖和存活。同时，它通过受体家族的受体Mer促进OC的激活。PRO的基因阻断减轻了骨髓瘤的负担，延长了携带系统性MM模型的小鼠的生存时间。重要的是，MM诱导的骨病在PROS被中和后几乎完全被废除。因此，阻断前轴有可能减轻骨髓瘤的负担，减少MM诱导的OC激活。此外，我们还发现PROS可诱导OC的免疫抑制表型。基于这些数据，我们建议对临床适用的小分子Mer抑制剂R992的潜在分子机制和治疗潜力进行详细的功能研究，以治疗MM，特别是骨病。此外，我们还将剖析两种不同的受体Ax1和Tyro3在破骨细胞形成中的作用。为此，我们将使用共培养和小鼠模型的MM与OC特异性阻断TAMR的遗传方法。此外，我们将评估TAMR阻滞剂对MM进展及其相关骨病和免疫抑制的治疗效果。最终，我们将通过分析PROS和TAMR与预后和MM诱发的骨病的关系，将我们的研究结果从长凳转移到床边。该项目将特别与L.Hofbauer(德累斯顿)和A.Garbe(德累斯顿)的小组联系在一起，我们将与他们形成骨免疫学网络。相反，我们将在我们的功能小鼠模型中研究MM诱导的骨病的新介质，这些介质来自于我们的功能性小鼠模型。

A hallmark of multiple myeloma (MM) is the reciprocal “vicious” interaction between PC and osteoclasts (OC). This cross-talk leads to disease progression, immunosuppression and osteolytic bone disease. Despite significant advances in the treatment of MM the disease remains incurable in the majority of patients. Therefore, the discovery of novel mechanisms promoting myeloma and its associated bone disease are still urgently needed. In this context, the development of an increased understanding of the interaction between myeloma cells, immune cells and bone cells is of special interest because immune cells hold great potential to destroy malignant cells. However, the regulation and therapeutic activation of anti-myeloma immune responses in the bone marrow is understudied.Our preliminary data show that Protein S (ProS) promotes the proliferation and survival of MM cells. At the same time, it fosters the activation of OC via the receptor Mer, which belongs to the TAM receptor family. Genetic blockade of ProS reduces myeloma burden and prolongs the survival of mice bearing a systemic MM model. Importantly, MM-induced bone disease is almost completely abrogated upon neutralization of ProS. Thus, the blockade of the ProS-Mer axis holds potential to reduce myeloma burden and decrease MM-induced OC activation. In addition, we found that ProS induces an immunosuppressive phenotype of OC. Based on these data we propose a detailed functional investigation of the underlying molecular mechanisms and of the therapeutic potential of the clinically applicable small molecule Mer inhibitor R992 for treatment of MM with a special focus on bone disease. In addition, we will dissect the role of the two alternative TAM receptors Axl and Tyro 3 in osteoclastogenesis. For this purpose, we will use co-cultures and mouse models of MM with OC-specific blockade of TAMR by genetic approaches. Furthermore, we will evaluate the therapeutic effect of TAMR blockade on MM progression as well as on its associated bone disease and immunosuppression. Ultimately, we will translate our findings from the bench to the bedside by analyzing the association of ProS and TAMR with prognosis and MM-induced bone disease.The project will be in particular linked to the groups of L. Hofbauer (Dresden) and A. Garbe (Dresden), with whom we will form an osteoimmunology network. By assessing overlapping cell types and molecular mediators we expect a significant knowledge gain concerning whether the interplay between bone and immune cells is via different or overlapping mechanisms in solid cancer versus MM. Furthermore, we will build a strong bidirectional link to D. Hose (Heidelberg), who will contribute a unique MM patient cohort allowing us to assess the association of the ProS/TAMR axis with MM bone disease. Conversely, we will investigate novel mediators of MM-induced bone disease derived from this patient cohort in our functional mouse models.