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的再生，包括干细胞定位调节和干细胞谱系定位改变、血管生成和成骨的解偶联以及促进溶骨的恶性循环。我们已经确定了几种新的靶向机制来调节骨髓瘤和MSC之间的接触所诱导的干细胞生态位和中胚层承诺，例如：(I)成骨和血管生成和脂肪生成的谱系承诺受损(ROR1，BMPER)；(Ii)诱导新的转移前生态位和竞争性劫持预形成的干细胞生态位(CXCR4/SDF-1，Ebf2，JAM2/3)；以及(Iii)骨髓瘤骨疾病的进展(KISS1R，通过GPR的促凋亡信号)。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定的骨髓瘤治疗。我们在第二个资助期的具体目标是以接触诱导/抑制的候选者和信号系统为靶点，以便(I)研究谱系承诺抑制物和血管生成解离剂的生物学相关性，(Ii)阐明骨髓瘤骨疾病中依赖于局部氧分压的生态位调节和T细胞反应的分子机制，以及(Iii)确定KISS1R系统与骨再生的相关性及其成像和部位特异性靶向的潜力。总体策略是使用2D细胞培养、骨髓BioVaSc设备中的3D共培养、临床前模型(例如MOPC315.BM)中的逐步表征来评估候选先导作为诊断和治疗目标，并在多发性骨髓瘤患者的人类材料中验证这些发现。这些研究应该典型地将骨骼和骨髓的利基整合到抗肿瘤策略中。重建骨骼和血液再生的利基环境和途径可能会赋予抗骨髓瘤的疗效。

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.