Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-1 provided imatinib resistance in chronic myeloid leukemia cells

Marta D Kolba, Wioleta Dudka, Monika Zaręba-Kozioł, Agata Kominek, Paolo Ronchi, Laura Turos, Piotr Chroscicki, Jakub Wlodarczyk, Yannick Schwab, Agata Klejman, Dominik Cysewski, Katja Srpan, Daniel M Davis, Katarzyna Piwocka

Research output: Contribution to journalArticlepeer-review

Abstract

Intercellular communication within the bone marrow niche significantly promotes leukemogenesis and provides protection of leukemic cells from therapy. Secreted factors, intercellular transfer of mitochondria and the receptor-ligand interactions have been shown as mediators of this protection. Here we report that tunneling nanotubes (TNTs) – long, thin membranous structures which have been identified as a novel mode of intercellular cross-talk – are formed in the presence of stroma and mediate transfer of cellular vesicles from stroma to leukemic cells. Importantly, transmission of vesicles via TNTs from stromal cells increases resistance of leukemic cells to the tyrosine kinase inhibitor, imatinib. Using correlative light-electron microscopy and electron tomography we show that stromal TNTs contain vesicles, provide membrane continuity and can be open-ended. Moreover, trans-SILAC studies to reveal the non-autonomous proteome showed that specific sets of proteins are transferred together with cellular vesicles from stroma to leukemic cells, with a potential role in survival and adaptation. Altogether, our findings provide evidence for the biological role of the TNT-mediated vesicle exchange between stroma and leukemic cells, implicating the direct vesicle and protein transfer in the stroma-provided protection of leukemic cells.
Original languageEnglish
JournalCell Death Dis
Volume10
Issue number817
Early online date28 Oct 2019
DOIs
Publication statusPublished - 2019

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