Chromosomal Translocation-derived Aberrant RAB22A Drives Osteosarcoma Metastasis

Osteosarcoma is one of the most aggressive cancer types. It tends to metastasize to lungs with poor prognosis, but the related molecular mechanism is poorly understood. Here, we identified new 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 (RAB22A1-38) with multiple inverse introns/untranslated regions of chromosome 20. The resulting translation products, named as RAB22A-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The RAB22A1-38 portion governs the function of RAB22A-NeoFs by binding to SmgGDS607, a GTP/GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS607, which induces the overactivity of RhoA and promotes metastasis. Disrupting the interaction between RAB22A-NeoF1 and SmgGDS607 by a designed peptide prevents lung metastasis in the orthotopic osteosarcoma metastasis model. Our findings provide a potential therapeutic strategy for osteosarcoma patients with lung metastases