Osteosarcoma (OS) is a leading cause of cancer-related death in pediatric patients. Mortality rates for this cancer have not changed substantially during the last three decades, due in part to the lack of an FDA-approved targeted therapy. An understanding of the etiology of OS is a critical need for developing new treatment options. Genomic sequencing studies did not find any dominant actionable targets. Our strategy is to identify the survival signals of OS cells that are related to the p53 pathway. In addition to human OS cell lines, we have been using mesenchymal stem cells (MSCs) as a model since they are the putative cell-of-origin of OS cells. During this review period, we have made several key advances. First, we showed that p53 represses RUNX2 expression in MSCs, and p53 loss predisposes these cells to osteoblast differentiation, providing an explanation for the clinical observation that OS is tightly associated with p53 loss. Second, we identified the CBFB/RUNX2 axis as a survival signal in OS cells. Third, we uncovered that in the context of p53 loss, oncogenes determine the types of sarcomas originating from MSCs. For example, the cFos-Sox9 axis promotes chondroblastic OS from p53 null MSCs. Future studies are focused on further investigating the pro-survival function of RUNX2 in OS. It is our hope that we will find vulnerabilities of OS in RUNX2-regulation gene expression that can be exploited for developing novel treatment of OS. We have recently ramped up our efforts to study translation dysregulation in breast cancer based on our discovery of a new function for CBFB in translational regulation of breast cancer. The CBFB gene is mutated in about 5 percent of breast tumors; however, its function in breast cancer had not been known. We were the first to report that CBFB has a tumor suppressive role in breast cancer. The underlying molecular mechanism was completely unexpected. In contrast to the well accepted view that CBFB is a transcription factor, we found that cytoplasmic CBFB directly regulates translation in breast cancer cells. Because transcriptional events are difficult to target, translation represents a vital step in gene expression for identifying cancer vulnerabilities. Indeed, our preliminary studies suggested that downstream events caused by deregulation of CBFB-mediated translation could be further exploited to identify vulnerabilities in breast cancer. Therefore, understanding CBFB-regulated translation in breast cancer has become a major focus of my research program. Ongoing efforts are concentrated on investigating the metabolic shift and autophagy dysregulation caused by CBFB defect in breast cells.
