Research Project
10004080
PROJECT SUMMARY The goal of this project is to understand developmental signaling pathways (DSPs) that are regulated by human cancer driver mutations in premalignant osteoblast progenitor (POP) and osteogenic sarcoma (OS) cells. Human OS represents a deadly skeletal malignancy found predominantly in children. The clinical outcomes for OS patients with recurrent tumors, or metastatic spread, are devastating. Elucidating OS biology is essential for developing effective new treatments. Several lines of evidence suggest that tumor protein p53 (TP53) mutations are major drivers in OS patients with Li- Fraumeni familial cancer syndrome, and in most of sporadic OS patients. It is unknown, however, how aberrant p53-regulated DSPs promote the proliferation and transformation of POP cells, as well as maintain self-renewal of OS stem cell and metastasis. Along with our collaborators, we have developed several authentic, genetically engineered mouse models of OS tumors that recapitulate the defining feature of human OS, which include cytogenetic complexity, gene expression signatures, histology, and metastatic behavior. These models provide a powerful tool for understanding the aforementioned clinical challenge and for developing novel therapeutic strategies. Our preliminary studies in mice and human OS cells found a connection between DSPs and tumorigenesis in the transformation of POP cells to their malignant counterpart. Validating those findings will significantly contribute to clinical applications. Based on these findings, we hypothesize that DSPs downstream of driver mutations play a critical role in the POP and OS population; moreover, perturbation of the crosstalk between drivers and DSPs may contribute to the pathogenesis of OS and cancer therapy. We will test this hypothesis through three specific aims. Aim1. What is the role of DSPs regulated by p53 loss of function (p53 LOF) in the development of OS? Aim2. Do DSPs play a critical role in the development of cells of POP and OS driven by Notch gain of function (Notch GOF)? With the completion of this work, we will have a more complete understanding of the molecular mechanism underlying the action of driver-regulated DSPs on POP and OS cells.
