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B. Gao



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    MA 15 - Lung Cancer Biology II (ID 670)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 15.13 - The Transfer of Exogenous UCHL-1 via Mesenchymal Lung Cancer Exosomes to Mediate Phenotypic Alterations of Recipients (ID 9094)

      15:45 - 17:30  |  Author(s): B. Gao

      • Abstract
      • Presentation
      • Slides

      Background:
      Cancer-derived exosomes are micro-vesicles released by tumor cells and are believed to be involved in intercellular signaling and communication. Recent evidence suggests exosomes help tumor cells invade neighboring tissues and prime metastatic sites for disease spread. Non-small cell lung cancer (NSCLC) is a highly metastatic disease and little is known about how tumor-derived exosomes may influence migration or invasion of lung cancer cells and prime metastatic niches.

      Method:
      Exosomes were recovered by a sequential centrifugation schema. Exosomes isolated from lung cancer cell line H1299, A549, H1993, and H2073, and non-malignant, immortalized human bronchial epithelial cell (HBEC) 3KT and 30KT were characterized. We examined the effects of cancer-derived exosomes on HBECs, oncogenically progressed HBECs (HBEC sh-p53+KRAS[v12]; HBEC3KTRL53) in vitro and their influence on metastasis in murine models. Mass spectrometry was performed to identify candidate proteins carried in tumor exosomes that induce phenotypic changes in recipient cells.

      Result:
      Cancer-derived exosomes but not HBEC-derived exosomes confer invasiveness and increased motility on recipient cells (HBEC3KT, HBEC3KTRL53) in wound healing and Boyden chamber assays. Mesenchymal NSCLC exosomes induce mesenchymal-like phenotypic changes (loss of EPCAM expression and upregulated EMT-transcriptional factors) in HBEC3KT in FACS and qRT-PCR analyses. Cancer-derived exosomes but not HBEC3KT exosomes enhance the lung endothelial permeability, promote lung metastasis, and recruit myeloid-derived suppressor cells in vivo. Mass spectrometry shows that H1299 exosomes contains a wide variety of deubiquitinating enzymes (DUBs) compared to HBEC3KT exosomes, and UCHL-1 (Ubiquitin carboxy-terminal hydrolase L1) is the most highly expressed DUB in H1299 exosomes. UCHL-1 expression is upregulated in mesenchymal NSCLC cells/exosomes, and HBEC3KT cells treated with mesenchymal NSCLC exosomes in vitro, and activated in metastatic sites after cancer-derived exosome treatment in vivo. UCHL-1 knockdown suppresses metastasis induced by cancer-derived exosomes. Exosomes derived from UCHL-1-knockdown H1299 show a decreased effect of the induction of migration, invasiveness, and epithelial/mesenchymal phenotypic changes on recipient cells.

      Conclusion:
      Mesenchymal NSCLCs-derived exosomes compared to HBECs-derived exosomes induced an increased migratory/invasive phenotype with lung vascular leakiness, metastatic niche formation, and higher xenograft tumor take rates. UHCL-1 was overexpressed only in mesenchymal NSCLCs/exosomes. UCHL-1 knockdown suppressed metastasis, and its exosomes also showed a decreased effect of the induction of tumor progression. These results suggest that understanding and targeting UCHL-1 likely as a key factor of mesenchymal NSCLC-derived exosome behavior could lead to novel therapeutic strategies.

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