Osteosarcoma is a type of aggressive malignant bone tumour that frequently metastasizes to lungs, resulting in poor prognosis. However, the molecular mechanisms of lung metastasis of osteosarcoma remain poorly understood. Here we identify exon–intron fusion genes in osteosarcoma cell lines and tissues. These fusion genes are derived from chromosomal translocations that juxtapose the coding region for amino acids 1–38 of Rab22a (Rab22a^1–38) with multiple inverted introns and untranslated regions of chromosome 20. The resulting translation products, designated Rab22a-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The Rab22a^1–38 moiety governs the function of Rab22a-NeoFs by binding to SmgGDS-607, a GTP–GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS-607, which induces increased activity of RhoA and promotes metastasis. Disrupting the interaction between Rab22a-NeoF1 and SmgGDS-607 with a synthetic peptide prevents lung metastasis in an orthotopic model of osteosarcoma. Our findings may provide a promising strategy for a subset of osteosarcoma patients with lung metastases.

骨肉瘤是一种侵袭性恶性骨肿瘤，经常转移到肺部，导致预后不良。然而，骨肉瘤肺转移的分子机制仍然知之甚少。在这里，我们鉴定了骨肉瘤细胞系和组织中的外显子 - 内含子融合基因。这些融合基因来源于染色体易位，这些易位将 Rab22a 的氨基酸 1-38 (Rab22a ^1-38 ) 的编码区与 20 号染色体的多个反向内含子和非翻译区并列。由此产生的翻译产物，称为 Rab22a-NeoFs，获得驱动骨肉瘤肺转移的能力。Rab22a ^1–38部分通过与 RhoA 的 GTP-GDP 交换因子 SmgGDS-607 结合来控制 Rab22a-NeoFs 的功能。这种关联促进了 GTP 结合的 RhoA 从 SmgGDS-607 的释放，从而诱导 RhoA 的活性增加并促进转移。用合成肽破坏 Rab22a-NeoF1 和 SmgGDS-607 之间的相互作用可防止骨肉瘤原位模型中的肺转移。我们的研究结果可能为一部分骨肉瘤肺转移患者提供有希望的策略。