In: Journal of Experimental & Clinical Cancer Research, 38 (2019), Nr. 132. S. 1-20. ISSN 1756-9966
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Abstract
Background: Cancer-initiating cell (CIC) exosomes (CIC-TEX) are suggested reprogramming Non-CIC. Mode of message transfer and engagement of CIC-markers being disputed, we elaborated the impact of CD44v6 and Tspan8 on the response of Non-CIC.
Methods: Non-metastasizing CD44v6- and Tspan8-knockdown (kd) pancreatic cancer cells served as Non-CIC. CIC-TEX coculture-induced changes were evaluated by deep-sequencing and functional assays. Tumor progression was surveyed during in vivo CIC-TEX treatment.
Results: Deep-sequencing of CIC-TEX-cocultured CD44v6kd-Non-CIC revealed pronounced mRNA changes in signaling, transport, transcription and translation; altered miRNA affected metabolism, signaling and transcription. CIC-TEX coculture-induced changes in Tspan8kd-Non-CIC mostly relied on CIC-TEX-Tspan8 being required for targeting. CIC-TEX transfer supported apoptosis resistance and significantly promoted epithelial mesenchymal transition, migration, invasion and (lymph)angiogenesis of the kd Non-CIC in vitro and in vivo, deep-sequencing allowing individual mRNA and miRNA assignment to altered functions. Importantly, CIC-TEX act as a hub, initiated by CD44v6-dependent RTK, GPCR and integrin activation and involving CD44v6-assisted transcription and RNA processing. Accordingly, a kinase inhibitor hampered CIC-TEX-fostered tumor progression, which was backed by an anti-Tspan8 blockade of CIC-TEX binding.
Conclusions: This in depth report on the in vitro and in vivo impact of CIC-TEX on CD44v6kd and Tspan8kd Non-CIC unravels hub CIC-TEX activity, highlighting a prominent contribution of the CIC-markers CD44v6 to signaling cascade activation, transcription, translation and miRNA processing in Non-CIC and of Tspan8 to CIC-TEX targeting. Blocking CIC-TEX binding/uptake and uptake-initiated target cell activation significantly mitigated the deleterious CIC-TEX impact on CD44v6kd and Tspan8kd Non-CIC.
Dokumententyp: | Artikel |
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Titel der Zeitschrift: | Journal of Experimental & Clinical Cancer Research |
Band: | 38 |
Nummer: | 132 |
Verlag: | BioMed Central ; Springer |
Ort der Veröffentlichung: | London ; Berlin, Heidelberg |
Erstellungsdatum: | 22 Mai 2019 15:24 |
Erscheinungsjahr: | 2019 |
ISSN: | 1756-9966 |
Seitenbereich: | S. 1-20 |
Institute/Einrichtungen: | Zentrale und Sonstige Einrichtungen > Europäisches Laboratorium für Molekularbiologie (EMBL)
Medizinische Fakultät Heidelberg und Uniklinikum > Chirurgische Universitätsklinik |
DDC-Sachgruppe: | 610 Medizin |
Freie Schlagwörter: | CD44v6, Tspan8, Pancreatic cancer stem cells, Exosome biogenesis, Exosome message transfer, Noncancer stem cell reprogramming |