Bone cancer is one of the most common primary malignancies in children and adolescents. Osteosarcoma
comprises almost 60% of the common histological subtypes of bone sarcoma. While the five-year survival rate of
non-metastatic disease hovers at approximately 70%, metastatic disease, most often to the lungs, is associated
with survival rates of 15% to 30%. Despite advances in surgery and multi-agent chemotherapy, lack of
understanding of the molecular mechanisms of osteosarcomagenesis has prevented significant improvement in
the survival of patients over the past 40 years. This malignancy makes osteosarcoma one of the leading causes
of cancer mortality among children and adolescents. Therefore, elucidation of the function of individual
osteosarcoma-associated genes (e.g., RB1 and p53 tumor suppressor genes) to explore the possible pathological
mechanisms involved in osteosarcoma initiation, development and progression is critical for future osteosarcoma
detection and treatment.
Induced pluripotent stem cells (iPSCs) is one of the most promising platforms recognized by cancer
researchers. Recently, several groups including us successfully apply patient-derived iPSCs to phenocopy cancer
features, explore disease mechanisms, and screen therapeutic drugs. These findings strongly suggest patient-
derived iPSCs is a feasible system to model and dissect cancer etiology. Patients with hereditary retinoblastoma
(RB), an inherited autosomal dominant cancer disorder caused by germline mutations/deletions in the RB1 tumor
suppressor gene, have increased >400 fold incidence of osteosarcoma, which provides a perfect model system
to study the role of RB1 in osteosarcomagenesis.
Our preliminary studies revealed that an increase of spliceosome genes in RB iPSC-derived osteoblasts.
These results lead to our central hypothesis that an altered spliceosome function is important for facilitating tumor
initiation and development in RB1-mutant osteosarcoma. Guided by strong preliminary data, we plan to utilize RB
patient-derived iPSC disease model to pursue three Specific Aims to elucidate the pathological mechanisms
involved in RB1-mutant osteosarcoma: (1) To elucidate how loss of RB1 contributes to upregulated spliceosome
gene expression. (2) To evaluate the therapeutic potential of splicing modulators for osteosarcoma treatment. (3)
To define the role of CUL9 in regulating RB1 function.
Collectively, our proposed research will broadly impact the osteosarcoma field by characterizing the
essential role of spliceosome in regulating RB1-mutant osteosarcoma development. These studies will also have
potential to uncover novel molecular mechanisms regulating RB1 proteolysis controlled by CUL9 tumor
suppressor. Successful completion of the proposed experiment will add valuable and novel insights to a broad
range of fields including cancer genetics, dysregulation of spliceosome gene expression, and ubiquitin-
proteasome proteolytic pathway, each of which bears potential clinical applications for osteosarcoma treatment.