Anti-myeloma strategies by re-establishing bone regeneration and hematopoietic niches

多发性骨髓瘤（MM）通过多种机制抑制骨和血液再生，包括干细胞龛调节与干细胞谱系定型改变，血管生成和骨生成的解偶联，以及促进溶骨性恶性循环。我们已经确定了几个新的调节骨髓瘤和MSC之间接触诱导的干细胞龛和中胚层定型的靶机制，如（I）骨生成的谱系定型受损，血管生成和脂肪生成改变（ROR 1，BMPER）;（II）诱导新的转移前小生境和竞争性劫持预先形成的干细胞小生境（CXCR 4/SDF-1，EBF 2，JAM 2/3）;和（III）骨髓瘤骨疾病的进展（KISS 1 R，通过GPR的促凋亡信号传导）。基于这些结果，我们假设这些靶点可以用于敏感的分子成像，恢复血液和骨再生以及特异性骨髓瘤治疗。我们第二个资助期的具体目标是靶向接触诱导/抑制的候选者和信号系统，以便（I）研究谱系定型抑制剂和血管生成崩解剂的生物学相关性，（II）阐明骨髓瘤骨病中取决于局部氧张力的生态位调节和T细胞应答的分子机制，和（III）确定KISS 1 R系统与骨再生的相关性及其成像和位点特异性靶向的潜力。一般策略是使用骨髓中BioVaSc器械中的2D细胞培养物、3D共培养物、临床前模型（例如MOPC315.BM）中的逐步表征评价作为诊断和治疗靶点的候选药物，并在MM患者的人体材料中验证这些结果。这些研究应典型地将骨和骨髓小生境整合到抗肿瘤策略中。重建骨和血液再生的小生境和途径可能会赋予抗骨髓瘤疗效。

Multiple myeloma (MM) inhibits bone and blood regeneration by various mechanisms, including stem cell niche conditioning with altered stem cell lineage commitment, uncoupling of angiogenesis and osteogenesis, and promotion of osteolytic vicious cycles. We have identified several new target mechanisms for modulating the stem cell niche and mesodermal commitment induced by contact between myeloma and MSC, such as (I) impaired lineage commitment for osteogenesis and altered angiogenesis and adipogenesis (ROR1, BMPER); (II) induction of new premetastatic niches and competitive hijacking of preformed stem cell niches (CXCR4/SDF-1, EBF2, JAM2/3); and (III) progression of myeloma bone disease (KISS1R, proapoptotic signaling via GPR). Based on these results we hypothesize that these targets can be addressed for sensitive molecular imaging, restoration of blood and bone regeneration and specific myeloma treatment. Our specific aims for the second funding period are to target contact-induced/repressed candidates and signaling systems in order to (I) investigate the biological relevance of inhibitors for lineage commitment and of disintegrators of angiogenesis, (II) to elucidate molecular mechanisms of niche modulation and T-cell response in myeloma bone disease depending on local oxygen tension, and (III) to define the relevance of the KISS1R system for bone regeneration and its potential for imaging and site-specific targeting. The general strategy is to evaluate lead candidates as diagnostic and therapeutic targets using stepwise characterization in 2D cell culture, 3D co-cultures in the BioVaSc device in bone marrow, preclinical models (e.g. MOPC315.BM) and validate these findings in human material from MM patients. These studies should paradigmatically integrate the bone and bone marrow niche into anti-tumor strategies. Reestablishing niches and pathways for bone and blood regeneration may confer anti-myeloma efficacy.