Vulnerabilities in osteosarcoma and breast cancer

骨肉瘤（OS）是儿童癌症相关死亡的主要原因。在过去的30年里，这种癌症的死亡率没有实质性的变化，部分原因是缺乏fda批准的靶向治疗。了解OS的病因是开发新的治疗方案的关键。基因组测序研究没有发现任何显性的可操作靶点。我们的策略是识别与p53通路相关的OS细胞存活信号。除了人类OS细胞系外，我们还使用间充质干细胞（MSCs）作为模型，因为它们被认为是OS细胞的起源细胞。在审查期间，我们取得了几项重要进展。首先，我们发现p53抑制MSCs中RUNX2的表达，p53缺失使这些细胞容易向成骨细胞分化，这就解释了临床观察到OS与p53缺失密切相关。其次，我们发现CBFB/RUNX2轴是OS细胞的存活信号。第三，我们发现在p53缺失的情况下，癌基因决定了源自MSCs的肉瘤的类型。例如，cFos-Sox9轴促进p53缺失的MSCs成软骨细胞移植。未来的研究重点是进一步研究RUNX2在OS中的促生存功能。我们希望能够在runx2调控基因表达中发现OS的漏洞，从而开发出新的OS治疗方法。基于我们发现CBFB在乳腺癌翻译调控中的新功能，我们最近加大了对乳腺癌翻译失调的研究力度。CBFB基因在大约5%的乳腺肿瘤中发生突变；然而，它在乳腺癌中的作用尚不清楚。我们首次报道了CBFB在乳腺癌中具有肿瘤抑制作用。其潜在的分子机制是完全出乎意料的。与CBFB是一种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的翻译。由于转录事件很难定位，翻译代表了基因表达中识别癌症易感性的重要一步。事实上，我们的初步研究表明，cbfb介导的翻译解除管制引起的下游事件可以进一步用于确定乳腺癌的脆弱性。因此，了解cbfb在乳腺癌中的调控翻译已成为我研究项目的主要重点。目前正在进行的研究集中在研究由乳腺细胞CBFB缺陷引起的代谢转移和自噬失调。

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, partly due to the lack of an FDA-approved targeted therapy. Understanding 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 OS cells' survival signals 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 critical 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. We hope that we will find vulnerabilities of OS in RUNX2-regulation gene expression that can be exploited for developing a 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 the 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 the CBFB defect in breast cells.