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@ARTICLE{Kyuno:143815,
author = {D. Kyuno and K. Zhao and M. Schnölzer$^*$ and J. Provaznik
and T. Hackert and M. Zöller},
title = {{C}laudin7-dependent exosome-promoted reprogramming of
nonmetastasizing tumor cells.},
journal = {International journal of cancer},
volume = {145},
number = {8},
issn = {1097-0215},
address = {Bognor Regis},
publisher = {Wiley-Liss},
reportid = {DKFZ-2019-01377},
pages = {2182-2200},
year = {2019},
abstract = {Claudin7 (cld7) is a cancer-initiating cell (CIC) marker in
gastrointestinal tumors, a cld7-knockdown (kd) being
accompanied by loss of tumor progression. Tumor exosomes
(TEX) restoring CIC activities, we explored the contribution
of cld7. This became particularly interesting, as tight
junction (TJ)- and glycolipid-enriched membrane domain
(GEM)-derived cld7 is recruited into distinct TEX. TEXs were
derived from CIC or cld7kd cells of a rat pancreatic and a
human colon cancer line. TEX derived from pancreatic cancer
cld7kd cells rescued with palmitoylation site-deficient cld7
(cld7mP) allowed selectively evaluating the contribution of
GEM-derived TEX, only palmitoylated cld7 being integrated
into GEM. Cld7 CIC-TEX promoted tumor cell dissemination and
metastatic growth without a major impact on proliferation,
apoptosis resistance and epithelial-mesenchymal transition.
Instead, migration, invasion and (lymph)angiogenesis were
strongly supported, only migration being selectively
fostered by GEM-derived cld7 TEX. CIC-TEX coculture of
cld7kd cells uncovered significant changes in the cld7kd
cell protein and miRNA profiles. However, changes did not
correspond to the CIC-TEX profile, CIC-TEX rather initiating
integrin, protease and RTK, particularly lymphangiogenic
receptor activation. CIC-TEX preferentially rescuing
cld7kd-associated defects in signal transduction was backed
up by an RTK inhibitor neutralizing the impact of CIC-TEX on
tumor progression. In conclusion, cld7 contributes to
selective steps of the metastatic cascade. Defects of cld7kd
and cld7mP cells in migration, invasion and
(lymph)angiogenesis are effaced by CIC-TEX that act by
signaling cascade activation. Accordingly, RTK inhibitors
are an efficient therapeutic defeating CIC-TEX.},
cin = {B100},
ddc = {610},
cid = {I:(DE-He78)B100-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30945750},
doi = {10.1002/ijc.32312},
url = {https://inrepo02.dkfz.de/record/143815},
}