Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes
Li Zhong, Dan Liao, Jingjing Li, Wenqiang Liu, Jingxuan Wang, Cuiling Zeng, Xin Wang, Zhiliang Cao, Ruhua Zhang, Miao Li, Kuntai Jiang, Yi-Xin Zeng, Jianhua Sui, Tiebang Kang
Abstract
Abstract 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.