期刊
SIGNAL TRANSDUCTION AND TARGETED THERAPY
卷 6, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41392-020-00414-1
关键词
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资金
- National Key Research and Development Program of China [2016YFA0500304]
- China Postdoctoral Science Foundation [2019M653225, 2020T130746]
- National Nature Science Foundation in China (NSFC) [81902738, 32070765, 81530081]
- Science and Technology Program of Guangzhou, China [201508020102]
The study revealed that the Rab22a-NeoF1 fusion protein in osteosarcoma promotes the formation of pulmonary pre-metastatic niche by exosomes and subsequently enhances lung metastasis. Additionally, exosomal PYK2 activates signaling pathways in recipient macrophages and osteosarcoma cells, leading to an increase in the M2 phenotype.
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 (RVLFLN142). 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.
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