Intracellular Communication of Gliomas via Exosomes

• Applicant: Privatdozent Dr. Franz Ricklefs
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267490279

• Final Report Year: 2017

Final Report Abstract

A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In Glioblastoma multiforme (GBM), 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.

Publications

• (2018) Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Science advances 4 (3) eaar2766
  Ricklefs, Franz L.; Alayo, Quazim; Krenzlin, Harald; Mahmoud, Ahmad B.; Speranza, Maria C.; Nakashima, Hiroshi; Hayes, Josie L.; Lee, Kyungheon; Balaj, Leonora; Passaro, Carmela; Rooj, Arun K.; Krasemann, Susanne; Carter, Bob S.; Chen, Clark C.; Steed, Ty
  
• „Therapies for Glioma: New Trends“, WFNOS Magazine, Issue 1 Volume 2, p57-59
  Ricklefs F, Chiocca EA
  
• “The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches.” Cell Reports 2016 May 31
  Mineo M, Ricklefs F, Root AK, Lyons SM, Ivanov P, Ansari KI, Nakano I, Chiocca EA, Godlewski J, Bronisz A
  
• ”Extracellular vesicles from high grade glioma exchange diverse pro-oncogenic signals that maintain intratumoral heterogeneity.“ Cancer Research 2016 Mar 24
  Ricklefs F, Mineo M, Rooj AK, Nakano I, Charest A, Weissleder R, Breakefield XO, Chiocca EA, Godlewski J, Bronisz A
  
• (2017): MicroRNA Signatures and Molecular Subtypes of Glioblastoma: The Role of Extracellular Transfer. In: Stem Cell Reports 8 (6), S. 1497–1505
  Godlweski J., Ferrer-Luna R., Rooj A., Mineo M., Ricklefs F., Yuji T., Salinska E., Nakano I., Lee H., Weissleder R., Beroukhim R., Chiocca EA., Bronisz A
  
• (2018): Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma. In: Neuro Oncol 20 (2), S. 225–235
  Speranza MC., Passaro C., Ricklefs F., Kasai K., Klein S., Nakashima H., Ahmed A., Nowicki O., Obi P., Bronisz A., Aguilar-Cordova E., Aguilar L., Guzik B., Breakefield XO., Weissleder R., Freeman G., Reardon D., Wen P., Chiocca EA., Lawler C.