Notch signaling drives multiple myeloma induced osteoclastogenesis

Michela Colombo, Katja Thümmler, Leonardo Mirandola, Silvia Garavelli, Katia Todoerti, Luana Apicella, Elisa Lazzari, Marialuigia Lancellotti, Natalia Platonova, Moeed Akbar, Maurizio Chiriva-Internati, Richard Soutar, Antonino Neri, Carl S. Goodyear, Raffaella Chiaramonte

Research output: Contribution to journalArticle

Abstract

Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors. The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance. Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact. Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities.

Original languageEnglish
Pages (from-to)10393-10406
Number of pages14
JournalOncotarget
Volume5
Issue number21
Publication statusPublished - 2014

Keywords

  • Bone disease
  • Jagged
  • Myeloma
  • Notch
  • RANKL

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Colombo, M., Thümmler, K., Mirandola, L., Garavelli, S., Todoerti, K., Apicella, L., Lazzari, E., Lancellotti, M., Platonova, N., Akbar, M., Chiriva-Internati, M., Soutar, R., Neri, A., Goodyear, C. S., & Chiaramonte, R. (2014). Notch signaling drives multiple myeloma induced osteoclastogenesis. Oncotarget, 5(21), 10393-10406.