Vulnerabilities in osteosarcoma and breast cancer

骨肉瘤（OS）是儿科患者癌症相关死亡的主要原因。在过去的三十年里，这种癌症的死亡率没有实质性变化，部分原因是缺乏FDA批准的靶向治疗。了解OS的病因是开发新治疗方案的关键需求。基因组测序研究没有发现任何显性的可操作的目标。我们的策略是识别与p53通路相关的OS细胞的存活信号。除了人OS细胞系之外，我们一直使用间充质干细胞（MSC）作为模型，因为它们是OS细胞的假定起源细胞。在本报告所述期间，我们取得了几项重要进展。首先，我们发现p53抑制了MSC中RUNX 2的表达，而p53缺失使这些细胞倾向于成骨细胞分化，这为临床观察到OS与p53缺失密切相关提供了解释。第二，我们鉴定了CBFB/RUNX 2轴作为OS细胞中的存活信号。第三，我们发现在p53缺失的情况下，癌基因决定了来源于MSC的肉瘤的类型。例如，cFos-Sox 9轴促进来自p53无效MSC的成软骨细胞OS。未来的研究集中在进一步调查的促生存功能的RUNX 2在OS。这是我们的希望，我们将发现OS的弱点，在RUNX 2调节基因的表达，可用于开发新的治疗OS。我们最近加大了我们的努力，研究乳腺癌的翻译失调的基础上，我们发现了一个新的功能CBFB在乳腺癌的翻译调节。CBFB基因在大约5%的乳腺肿瘤中发生突变;然而，它在乳腺癌中的功能尚不清楚。我们是第一个报道CBFB在乳腺癌中具有肿瘤抑制作用的人。其潜在的分子机制完全出乎意料。与CBFB是转录因子的公认观点相反，我们发现细胞质CBFB直接调节乳腺癌细胞中的翻译。由于转录事件难以靶向，翻译是基因表达中识别癌症脆弱性的重要步骤。事实上，我们的初步研究表明，由CBFB介导的翻译失调引起的下游事件可以进一步用于识别乳腺癌的脆弱性。因此，了解乳腺癌中CBFB调节的翻译已成为我研究计划的主要重点。正在进行的努力集中在研究乳腺细胞中CBFB缺陷引起的代谢转变和自噬失调。

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.