Tumour exosomes from cells harbouring PTPRZ1–MET fusion contribute to a malignant phenotype and temozolomide chemoresistance in glioblastoma

Abstract

Exosomes are carriers of pro-tumorigenic factors that participate in glioblastoma (GBM) progression, and many fusion genes are strong driver mutations in neoplasia and are involved in tumorigenesis. However, the ability of fusion genes to be transduced by exosomes is unknown. We characterized exosomes from GBM cells harbouring and not harbouring PTPRZ1–MET fusion (ZM fusion). We also determined the effect of the exosomes from ZM fusion cells (ZM exosomes) on pro-oncogenic secretions and showed that ZM exosomes are internalized by the recipient cells. In addition, we studied the effect of ZM exosome-mediated intercellular communication in the GBM microenvironment. MET proto-oncogene expression was higher in ZM exosomes. Moreover, phosphorylated MET was detected only in ZM exosomes and not in exosomes released by non-ZM fusion GBM cells. ZM exosomes transferred to non-ZM fusion GBM cells and normal human astrocytes altered gene expression and induced epithelial–mesenchymal transition. The uptake of ZM exosomes also induced an exosome-dependent phenotype defined by GBM cell migration and invasion, neurosphere growth and angiogenesis. In addition, ZM exosomes conferred temozolomide resistance to the GBM cells, and exosome-derived ZM fusion network proteins targeted multiple pro-oncogenic effectors in recipient cells within the GBM microenvironment. Our findings show that exosomes mediate the aggressive character of GBM and demonstrate the role of ZM fusion in the exacerbation of this effect. These findings have possible implications for the foundation of gene fusion-based therapy for managing GBM.

Cisplatin-Resistant Gastric Cancer Cells Promote the Chemoresistance of Cisplatin-Sensitive Cells via Exosomal RPS3 Mediated PI3K-Akt-cofilin-1 Signaling Axis

“…Colon cancer cell exosomes highly enriched in Nterminal truncated isoforms of p73 mRNA were able to confer drug resistance on recipient cells [19]. Exosomes from glioblastoma cancer cells harboring a protein tyrosine phosphatase receptor type Z1MET fusion conferred temozolomide resistance on parental cells [20]. These ndings demonstrated that exosomes could transfer intercellular drug resistance from drugresistant to drugsensitive cancer cells.…”

“…Increasing evidence suggests that tumor cellderived exosomes provide critical signals in the development of chemoresistance [810]. Several studies have revealed that the delivery of key molecules by exosomes to tumor cells could lead to chemoresistance [19,20]. Among the main components in exosomal cargo, some molecules have been discovered acting as the vital regulating effect on chemoresistance [21,22].…”

Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor

“…Nevertheless, our study provided an alternative therapeutic strategy for patients who have developed recurrent disease under TMZ-based standard therapy. Moreover, MET and ZM fusion are critical for chemoresistance in GBM (Huang et al, 2016;Zeng et al, 2017), and knock down of MET sensitizes tumor cell lines in response to TMZ treatment . Given the lack of therapeutic options for recurrent tumor under TMZ treatment, our study has provided a promising therapeutic strategy of PLB-1001 mono-and combinatorial treatments with TMZ chemotherapy for patients with MET alterations.…”

Exosomes play roles in sequential processes of tumor metastasis

“…However, the purpose for the exosome‐induced oncogenic transfer is largely undetermined, neither is the manner that this type of oncogenic transfer changes tumor growth and metastasis is occurring permanently or transiently. Although future explorations are needed, some researchers suggest it may relate to tumor chemoresistance, with recent evidence in glioblastoma demonstrated exosomes from cells harboring PTPRZ1‐MET fusion contribute to a malignant phenotype and temozolomide chemoresistance …”