Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the pro-tumorigenic activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not rely only on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV pro-tumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behaviour of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2 dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockage of NOTCH activation by gamma-Secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the pro-tumorigenic role of EV in MM as well as other tumors.

Extracellular vesicles mediate the communication between multiple myeloma and bone marrow microenvironment in a NOTCH dependent way / D. Giannandrea, N. Platonova, M. Colombo, M. Mazzola, V. Citro, R. Adami, F. Maltoni, S. Ancona, V. Dolo, I. Giusti, A. Basile, A. Pistocchi, L. Cantone, V. Bollati, L. Casati, E. Calzavara, M. Turrini, E. Lesma, R. Chiaramonte. - In: HAEMATOLOGICA. - ISSN 1592-8721. - 107:9(2022 Sep), pp. 1-12. [10.3324/haematol.2021.279716]

Extracellular vesicles mediate the communication between multiple myeloma and bone marrow microenvironment in a NOTCH dependent way

D. Giannandrea
Primo
;
N. Platonova;M. Colombo;M. Mazzola;V. Citro;R. Adami;S. Ancona;A. Basile;A. Pistocchi;L. Cantone;V. Bollati;L. Casati;E. Lesma;R. Chiaramonte
Ultimo
2022

Abstract

Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the pro-tumorigenic activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not rely only on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV pro-tumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behaviour of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2 dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockage of NOTCH activation by gamma-Secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the pro-tumorigenic role of EV in MM as well as other tumors.
Settore MED/04 - Patologia Generale
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
Settore BIO/14 - Farmacologia
Settore BIO/13 - Biologia Applicata
ASS_NAZ20RCHIA_01 - Impact of Notch signaling on extracellular vesicles-mediated tumor progression in multiple myeloma (3º anno) - CHIARAMONTE, RAFFAELLA - ASS_NAZ - Bandi da Associazioni e altri Finanziatori privati nazionali - 2020
10-mar-2022
https://haematologica.org/article/view/haematol.2021.279716
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/916322
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