Notch activation as a driver of osteogenic sarcoma.

TitleNotch activation as a driver of osteogenic sarcoma.
Publication TypeJournal Article
Year of Publication2014
AuthorsTao, J, Jiang, M-M, Jiang, L, Salvo, JS, Zeng, H-C, Dawson, B, Bertin, TK, Rao, PH, Chen, R, Donehower, LA, Gannon, F, Lee, BH
JournalCancer Cell
Volume26
Issue3
Pagination390-401
Date Published2014 Sep 8
ISSN1878-3686
KeywordsAnimals, Bone Neoplasms, Carcinogenesis, Cell Line, Tumor, Humans, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Nude, Mice, Transgenic, Neoplasm Transplantation, Osteoblasts, Osteosarcoma, Protein Structure, Tertiary, Receptor, Notch1, Transcriptome
Abstract

Osteogenic sarcoma (OS) is a deadly skeletal malignancy whose cause is unknown. We report here a mouse model of OS based on conditional expression of the intracellular domain of Notch1 (NICD). Expression of the NICD in immature osteoblasts was sufficient to drive the formation of bone tumors, including OS, with complete penetrance. These tumors display features of human OS; namely, histopathology, cytogenetic complexity, and metastatic potential. We show that Notch activation combined with loss of p53 synergistically accelerates OS development in mice, although p53-driven OS is not Rbpj dependent, which demonstrates a dual dominance of the Notch oncogene and p53 mutation in the development of OS. Using this model, we also reveal the osteoblasts as the potential sources of OS.

DOI10.1016/j.ccr.2014.07.023
Alternate JournalCancer Cell
PubMed ID25203324
PubMed Central IDPMC4159617
Grant ListR01 DE016990 / DE / NIDCR NIH HHS / United States
HD022657 / HD / NICHD NIH HHS / United States
AI036211 / AI / NIAID NIH HHS / United States
P01 HD022657 / HD / NICHD NIH HHS / United States
HD024064 / HD / NICHD NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
DE016990 / DE / NIDCR NIH HHS / United States
R03 AR061565 / AR / NIAMS NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
AR061565 / AR / NIAMS NIH HHS / United States
T32 EY007102 / EY / NEI NIH HHS / United States
P01 HD070394 / HD / NICHD NIH HHS / United States
RR024574 / RR / NCRR NIH HHS / United States