Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity

Abstract

A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In high grade gliomas (HGG), distinct hierarchical cell populations arise from different glioma stem-like cell (GSC) subpopulations. Extracellular vesicles (EV) shed by cells may serve as conduits of genetic and signaling communications, however, little is known about how HGG heterogeneity may impact EV content and activity. In this study, we performed a proteomic analysis of EV isolated from patient-derived GSC of either proneural or mesenchymal subtypes. EV signatures were heterogeneous, but reflected the molecular make-up of the GSC and consistently clustered into the two subtypes. EV-borne protein cargoes transferred between proneural and mesenchymal GSC increased pro-tumorigenic behaviors in vitro and in vivo. Clinically, analyses of HGG patient data from the TCGA database revealed that proneural tumors with mesenchymal EV signatures or mesenchymal tumors with proneural EV signatures were both associated with worse outcomes, suggesting influences by the proportion of tumor cells of varying subtypes in tumors. Collectively, our findings illuminate the heterogeneity among tumor EV and the complexity of HGG heterogeneity which these EV help maintain.

Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587

“…A recent report demonstrated that GSC-derived extracellular vesicles support intratumoral heterogeneity and that GSCs of the mesenchymal subtype had an increased proliferative effect on proneural subtype GSCs whereas treatment with self-exosomes had no effect [28]. Consistent with this report, we observed minimal effects on GSC growth when treated with self-derived exosomes.…”

Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell‐stimulating activities

“…Likewise, the generality of EV properties across larger panels of GBM and GSC isolates or subtypes, and their representation in intact tissues are still to be addressed more fully, and are currently under study. Moreover, therapy-induced evolution of GSCs [55] is likely to impact EV profiles, as we recently documented [56], while intra-tumoural interactions of different GSC population may also involve EV-dependent signals [28]. …”

The Molecular Connections between Lung and Pancreatic Cancer Metastases: are we not seeing the Forest for the Trees?

“…Suppression of immune cells (dendritic, NK-, and T-cells) through exosome communication plays an important role in tumor progression [217]. In the lung, immunosuppression by alveolar macrophages is a normal physiological, homeostatic function, and it must be to handle the constant onslaught of antigens through breathing [295]. Homeostatic balance between immunosuppression and immunoresponsiveness in the lung becomes dysregulated in tumor progression [148,163].…”