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

• Published in: Cell death & disease Vol. 10; no. 11; pp. 817 - 16
• Main Authors: Kolba, Marta D., Dudka, Wioleta, Zaręba-Kozioł, Monika, Kominek, Agata, Ronchi, Paolo, Turos, Laura, Chroscicki, Piotr, Wlodarczyk, Jakub, Schwab, Yannick, Klejman, Agata, Cysewski, Dominik, Srpan, Katja, Davis, Daniel M., Piwocka, Katarzyna
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.10.2019; Springer Nature B.V
• Subjects: 101/58; 13; 13/106; 13/2; 13/31; 13/89; 14; 14/28; 14/63; 631/67/327; 631/80/304; 692/699/1541; Antibodies; Apoptosis; Biochemistry; Biological Transport - genetics; Biomedical and Life Sciences; Bone marrow; Cell Biology; Cell Communication - drug effects; Cell Culture; Cell Line, Tumor; Cell signaling; Chronic myeloid leukemia; Drug Resistance, Neoplasm - genetics; Electron microscopy; Enzyme inhibitors; Flow cytometry; Humans; Imatinib; Imatinib Mesylate - chemistry; Imatinib Mesylate - pharmacology; Immunology; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemogenesis; Life Sciences; Membrane vesicles; Microscopy; Microscopy, Electron; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; Myeloid leukemia; Nanotubes; Nanotubes - chemistry; Protein-tyrosine kinase; Proteins; Proteomes; Software; Stromal cells; Stromal Cells - drug effects; Stromal Cells - ultrastructure; Targeted cancer therapy; Tomography
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2045-8

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 with the cell bodies 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 stromal 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 stromal and leukemic cells, implicating the direct vesicle and protein transfer in the stroma-provided protection of leukemic cells.