肺部是骨肉瘤 (OS) 最常见的转移部位。尽管我们在开发治疗实体恶性肿瘤的靶向疗法方面取得了进展，但广泛作用的化疗仍然是 OS 的一线治疗方法。在分析已批准的治疗非 OS 恶性肿瘤的疗效时，我们之前发现组蛋白脱乙酰酶 1 和 2（HDAC1 和 2）抑制剂罗米地辛可有效治疗已确定的肺转移性 OS。然而，罗米地辛已注意到对人类的毒性，因此我们的目的是确定 HDAC1/2 介导 OS 进展的主要机制，以识别更具选择性的药物靶点/途径。罗米地辛处理的 OS 细胞的微阵列和蛋白质组学分析显示，神经毡蛋白-1 (NRP1) 受到显着抑制，神经毡蛋白-1 是已知的癌细胞迁移和侵袭的调节因子。 NRP1 沉默可显着降低体外 OS 增殖、迁移、侵袭和粘附。更引人注目的是，在体内，减少 NRP1 表达可显着减轻两个独立模型（K7M2 和 SAOS-LM7）中 OS 的肺转移潜力。从机制上讲，我们的数据表明 NRP1 通过下调迁移机制（即 SRC、FAK 和 ROCK1 表达/活性）介导这种效应，这部分与 NRP1 与整合素 β 1 (ITGB1) 的相互作用有关。总之，我们的数据表明，罗米地辛对 NRP1 的下调显着降低了 OS 细胞在肺部播种和建立转移的能力，并且用选择性抑制剂靶向 NRP1 或其效应子可能是预防这一致命方面的可行方法。疾病。版权所有 © 2024。由 Elsevier B.V. 出版

The lungs represent the most common site of metastasis for osteosarcoma (OS). Despite our advances in developing targeted therapies for treating solid malignancies, broad acting chemotherapies remain the first line treatment for OS. In assaying the efficacy of approved therapeutics for non-OS malignancies, we previously identified the histone deacetylase 1 and 2 (HDAC1 and 2) inhibitor, romidepsin, as effective for the treatment of established lung metastatic OS. Yet, romidepsin has noted toxicities in humans and so here we aimed to define the primary mechanisms through which HDAC1/2 mediate OS progression to identify more selective druggable targets/pathways. Microarray and proteomics analyses of romidepsin treated OS cells revealed a significant suppression of neuropilin-1 (NRP1), a known regulator of cancer cell migration and invasion. Silencing of NRP1 significantly reduced OS proliferation, migration, invasion and adhesion in vitro. More strikingly, in vivo, reduced NRP1 expression significantly mitigated the lung metastatic potential of OS in two independent models (K7M2 and SAOS-LM7). Mechanistically, our data point to NRP1 mediating this effect via the down regulation of migration machinery, namely SRC, FAK and ROCK1 expression/activity, that is in part, related to NRP1 interaction with integrin beta 1 (ITGB1). In summary, our data indicate that romidepsin down regulation of NRP1 significantly mitigates the ability of OS cells to seed the lung and establish metastases, and that targeting NRP1 or its effectors with selective inhibitors may be a viable means with which to prevent this deadly aspect of the disease.Copyright © 2024. Published by Elsevier B.V.