Notch Activation as a Driver of Osteogenic Sarcoma

Abstract

Summary 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.

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

“…Our observation that NICD1 alone is not sufficient to drive prostate cancer initiation but instead synergizes with other pathways that can initiate only low-grade PIN lesions to drive prostate adenocarcinoma suggests that the Notch 1 receptor has a critical role in the progression of prostate cancer. These results are consistent with previous findings in osteogenic sarcoma and lung adenocarcinoma in which NICD1 strongly synergizes with p53 loss or Myc overexpression to accelerate tumor progression (49,50).…”

Cancer stem cells in osteosarcoma

“…Osteosarcoma is a vascularized tumour characterized by typical osteoid matrix formed by cancer cells (Figures 1D,E). Evidence comes predominantly from in vivo studies using MSCs and/or osteoprogenitors in which for example mutations in genes such as P53 and RB and/or aberrant Hedgehog and NOTCH signalling were shown to induce osteosarcoma (7)(8)(9). The terminology of 'cancer stem cells' is still under debate with the association to stem cells remaining controversial.…”

Deciphering signaling networks in osteosarcoma pathobiology

“…63 Moreover, a recent report provides evidence that Notch is not only altered during OS development but represents a driver of transformation in bone cells. 66 Restricted expression of intracellular domain of Notch in mice osteoblasts induced bone tumor formation, exhibiting histopathologic features typical of an aggressive OS tumor. 66 Cell lines were isolated from these mice, were immortalized and finally injected into nude mice creating new OS-like tumors between 14 and 28 days.…”