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

28 Citations (Scopus)

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

Fingerprint

Multiple Myeloma
Osteogenesis
Osteoclasts
Ligands
Notch2 Receptor
Neoplasms
Bone Marrow
Autocrine Communication
Biological Phenomena
Bone Diseases
Bone Resorption
Stromal Cells
Up-Regulation
Pharmacology
Morbidity
Bone and Bones

Keywords

  • Bone disease
  • Jagged
  • Myeloma
  • Notch
  • RANKL

ASJC Scopus subject areas

  • Oncology

Cite this

Colombo, M., Thümmler, K., Mirandola, L., Garavelli, S., Todoerti, K., Apicella, L., ... Chiaramonte, R. (2014). Notch signaling drives multiple myeloma induced osteoclastogenesis. Oncotarget, 5(21), 10393-10406.

Notch signaling drives multiple myeloma induced osteoclastogenesis. / Colombo, Michela; Thümmler, Katja; Mirandola, Leonardo; Garavelli, Silvia; Todoerti, Katia; Apicella, Luana; Lazzari, Elisa; Lancellotti, Marialuigia; Platonova, Natalia; Akbar, Moeed; Chiriva-Internati, Maurizio; Soutar, Richard; Neri, Antonino; Goodyear, Carl S.; Chiaramonte, Raffaella.

In: Oncotarget, Vol. 5, No. 21, 2014, p. 10393-10406.

Research output: Contribution to journalArticle

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, CS & Chiaramonte, R 2014, 'Notch signaling drives multiple myeloma induced osteoclastogenesis', Oncotarget, vol. 5, no. 21, pp. 10393-10406.
Colombo M, Thümmler K, Mirandola L, Garavelli S, Todoerti K, Apicella L et al. Notch signaling drives multiple myeloma induced osteoclastogenesis. Oncotarget. 2014;5(21):10393-10406.
Colombo, Michela ; Thümmler, Katja ; Mirandola, Leonardo ; Garavelli, Silvia ; Todoerti, Katia ; Apicella, Luana ; Lazzari, Elisa ; Lancellotti, Marialuigia ; Platonova, Natalia ; Akbar, Moeed ; Chiriva-Internati, Maurizio ; Soutar, Richard ; Neri, Antonino ; Goodyear, Carl S. ; Chiaramonte, Raffaella. / Notch signaling drives multiple myeloma induced osteoclastogenesis. In: Oncotarget. 2014 ; Vol. 5, No. 21. pp. 10393-10406.
@article{8b2d129fb9134704a5cdea6241afd746,
title = "Notch signaling drives multiple myeloma induced osteoclastogenesis",
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.",
keywords = "Bone disease, Jagged, Myeloma, Notch, RANKL",
author = "Michela Colombo and Katja Th{\"u}mmler and Leonardo Mirandola and Silvia Garavelli and Katia Todoerti and Luana Apicella and Elisa Lazzari and Marialuigia Lancellotti and Natalia Platonova and Moeed Akbar and Maurizio Chiriva-Internati and Richard Soutar and Antonino Neri and Goodyear, {Carl S.} and Raffaella Chiaramonte",
year = "2014",
language = "English",
volume = "5",
pages = "10393--10406",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "21",

}

TY - JOUR

T1 - Notch signaling drives multiple myeloma induced osteoclastogenesis

AU - Colombo, Michela

AU - Thümmler, Katja

AU - Mirandola, Leonardo

AU - Garavelli, Silvia

AU - Todoerti, Katia

AU - Apicella, Luana

AU - Lazzari, Elisa

AU - Lancellotti, Marialuigia

AU - Platonova, Natalia

AU - Akbar, Moeed

AU - Chiriva-Internati, Maurizio

AU - Soutar, Richard

AU - Neri, Antonino

AU - Goodyear, Carl S.

AU - Chiaramonte, Raffaella

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Bone disease

KW - Jagged

KW - Myeloma

KW - Notch

KW - RANKL

UR - http://www.scopus.com/inward/record.url?scp=84916899853&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84916899853&partnerID=8YFLogxK

M3 - Article

VL - 5

SP - 10393

EP - 10406

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 21

ER -