Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes

It remains unknown for decades how some of the therapeutic fusion proteins positive in a small percentage of cancer cells account for patient outcome.Here,we report that osteosarcoma Rab22a-NeoF1 fusion protein,together with its binding partner PYK2,is sorted into exosomes by HSP90 via its KFERQ-like motif(RVLFLN^(142)).The exosomal Rab22a-NeoF1 fusion protein facilitates the pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages.The exosomal PYK2 activates RhoA in its negative recipient osteosarcoma cells and induces signal transducer and activator of transcription 3 activation in its recipient macrophages to increase M2 phenotype.Consequently,lung metastases of its recipient osteosarcoma cells are promoted by this exosomal Rab22a-NeoF1 fusion protein,and this event can be targeted by disrupting its interaction with PYK2 using a designed internalizing RGD peptide.