eprintid: 26227
rev_number: 14
eprint_status: archive
userid: 1589
dir: disk0/00/02/62/27
datestamp: 2019-05-22 15:24:49
lastmod: 2024-03-03 22:52:09
status_changed: 2019-05-22 15:24:49
type: article
metadata_visibility: show
creators_name: Wang, Zhe
creators_name: Sun, Hanxue
creators_name: Provaznik, Jan
creators_name: Hackert, Thilo
creators_name: Zöller, Margot
title: Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming
subjects: 610
divisions: 850800
divisions: 910200
keywords: CD44v6, Tspan8, Pancreatic cancer stem cells, Exosome biogenesis, Exosome message transfer, Noncancer stem cell reprogramming
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.
date: 2019
publisher: BioMed Central ; Springer
id_scheme: DOI
ppn_swb: 166628887X
own_urn: urn:nbn:de:bsz:16-heidok-262275
language: eng
bibsort: WANGZHEPANCREATIC2019
full_text_status: public
publication: Journal of Experimental & Clinical Cancer Research
volume: 38
number: 132
place_of_pub: London ; Berlin, Heidelberg
pagerange: 1-20
issn: 1756-9966
citation:   Wang, Zhe ; Sun, Hanxue ; Provaznik, Jan ; Hackert, Thilo ; Zöller, Margot  (2019) Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming.  Journal of Experimental & Clinical Cancer Research, 38 (132).  pp. 1-20.  ISSN 1756-9966     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/26227/1/13046_2019_Article_1129.pdf