# Dissecting of develomental signaling pathways in bone development and osteosarcoma

> **NIH NIH P20** · SANFORD RESEARCH/USD · 2020 · $306,204

## Abstract

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.

## Key facts

- **NIH application ID:** 10004080
- **Project number:** 5P20GM103620-08
- **Recipient organization:** SANFORD RESEARCH/USD
- **Principal Investigator:** Jianning Tao
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,204
- **Award type:** 5
- **Project period:** 2013-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004080

## Citation

> US National Institutes of Health, RePORTER application 10004080, Dissecting of develomental signaling pathways in bone development and osteosarcoma (5P20GM103620-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10004080. Licensed CC0.

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