Claudin7-dependent exosome-promoted reprogramming of nonmetastasizing tumor cells

• Verfasst von: Kyuno, Daisuke [VerfasserIn]
• Verfasst von: Zhao, Kun [VerfasserIn]
• Verfasst von: Schnölzer, Martina [VerfasserIn]
• Verfasst von: Hackert, Thilo [VerfasserIn]
• Verfasst von: Zöller, Margot [VerfasserIn]
• Titel: Claudin7-dependent exosome-promoted reprogramming of nonmetastasizing tumor cells
• Verf.angabe: Daisuke Kyuno, Kun Zhao, Martina Schnölzer, Jan Provaznik, Thilo Hackert and Margot Zöller
• E-Jahr: 2019
• Jahr: 04 April 2019
• Umfang: 19 S.
• Fussnoten: Gesehen am 21.10.2019
• Titel Quelle: Enthalten in: International journal of cancer
• Ort Quelle: Bognor Regis : Wiley-Liss, 1966
• Jahr Quelle: 2019
• Band/Heft Quelle: 145(2019), 8, Seite 2182-2200
• ISSN Quelle: 1097-0215
• DOI: doi:10.1002/ijc.32312
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: claudin7
• Sach-SW: colorectal cancer
• Sach-SW: pancreatic cancer
• Sach-SW: tumor cell reprogramming
• Sach-SW: tumor exosomes
• K10plus-PPN: 1679239120

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.