Page 184 - Haematologica Vol. 107 - September 2022

ARTICLE - Plasma Cell Disorders
Extracellular vesicles mediate the communication between multiple myeloma and bone marrow microenvironment in a NOTCH dependent way
Domenica Giannandrea,1 Natalia Platonova,1 Michela Colombo,1 Mara Mazzola,2 Valentina Citro,1 Raffaella Adami,1 Filippo Maltoni,1 Silvia Ancona,1 Vincenza Dolo,3 Ilaria Giusti,3 Andrea Basile,4 Anna Pistocchi,2 Laura Cantone,5 Valentina Bollati,5 Lavinia Casati,1 Elisabetta Calzavara,6 Mauro Turrini,6 Elena Lesma1 and Raffaella Chiaramonte1
1Department of Health Sciences, Università degli Studi di Milano, Milano; 2Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano; 3Department of Life, Health and Environment Sciences, Università degli Studi dell’Aquila, L’Aquila; 4Department of Oncology and Hematology-Oncology, Università degli Studi di Milano, Milano; 5Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano and 6Division of Hematology, Valduce Hospital, Como, Italy
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 protumorigenic 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 only rely 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 protumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behavior 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 af- fect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockade of NOTCH activation by γ-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 protumorigenic role of EV in MM as well as other tumors.
Correspondence: R. Chiaromonte raffaella.chiaramonte@unimi.it
Received: Accepted: Prepublished:
August 11, 2021. March 2, 2022. March 10, 2022.
https://doi.org/10.3324/haematol.2021.279716
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
Multiple myeloma (MM) is a clonal plasma cell neoplasm representing alone 13% of all hematological malignancies.1 Despite the development of new therapies, MM still re- mains incurable,2 mainly due to MM cell ability to shape the bone marrow (BM) niche sustaining tumor progres- sion. Upon the localization in the BM, MM cells establish anomalous signaling loops with the neighboring cells and "educate" BM-residing non-tumor cells to support differ- ent steps of MM progression, including tumor cell growth, survival, angiogenesis, and bone osteolysis.3
In this complex picture, extracellular vesicles (EV) are new key players recently come to light. EV include a hetero- geneous group of cell-derived membranous structures classified into two main subtypes according to their ori-
gin. Exosomes, the smaller ones, originate from the en- dosomal system, while the larger vesicles are shed from the plasma cell membrane. Due to the difficulty to distin- guish these subtypes based on their origin, a recent posi- tion statement of the International Society for Extracellular Vesicles has suggested a distinction based on their size: i.e., small EV <200 nm and large EV >200 nm.4
EV are key mediators in the communication between tumor and stroma due to their ability to transport proteins and RNA.5 Circulating EV from MM patients display char- acteristic size distribution and concentration,6,7 and their microRNA (miRNA) cargo is prognostic in MM.8-10 Recent evidence indicates that MM cell-derived EV (MM-EV) modulate the BM niche, promoting angiogenesis, immu- nosuppression,11 and bone disease.12 Additionally, several
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