Understanding phosphate metabolism in cancer and metastasis

描述（由申请人提供）：肿瘤细胞的代谢重新布线通常被认为是癌症的标志，并且广泛认识到改变的葡萄糖和谷氨酰胺代谢驱动癌细胞增殖。我们假设，类似的情况也存在于 肿瘤细胞的磷需求：快速分裂的细胞应该依赖于磷酸盐的持续供应，并表现出改变的磷酸盐代谢。此外，我们认为局部高浓度的无机磷酸盐有助于溶骨性骨转移的高增殖微环境，并促进转移进展。迄今为止，对细胞内磷酸盐代谢知之甚少，并且不可能将细胞内磷酸盐水平和随后的磷酸盐代谢变化与肿瘤细胞增殖增加相关联。为了阐明是否存在“磷酸盐成瘾”的情况，迫切需要开发新的工具，这也是当前提案的目标。我们的实验室使用合成化学与细胞生物学和代谢组学相结合的跨学科方法，在骨转移的背景下解决了这一假设。我们正在开发小分子荧光磷酸盐传感器，以测量骨质溶解过程中的磷酸盐释放和邻近转移性乳腺癌细胞的磷酸盐摄取。此外，我们正在确定这些细胞的代谢网络如何处理骨微环境中的磷酸盐过剩。应用我们实验室新开发的捕获试剂来富集磷酸代谢组，结合全球代谢组学，将提供大量关于磷酸盐依赖性代谢重新布线的信息。总的来说，我们希望改变磷酸盐的看法：而不是将磷酸盐视为被动的构建块，它应该被认为是细胞代谢和行为的主动调节剂。了解成功定植的代谢要求可以为已经确定转移的患者开发有效的治疗方法。这些疗法是迫切需要的，因为肿瘤一旦转移到骨通常被认为是不可治愈的。

DESCRIPTION (provided by applicant): Metabolic rewiring of tumor cells is generally regarded as a cancer hallmark, and it is widely appreciated that altered glucose and glutamine metabolism drives cancer cell proliferation. We hypothesize that a similar situation exists for the phosphorus needs of tumor cells: Rapidly dividing cells should rely on a constant supply of phosphate and exhibit altered phosphate metabolism. Furthermore, we posit that the high local concentration of inorganic phosphate contributes to the highly prolific microenvironment in osteolytic bone metastasis and promotes metastasis progression. To date, very little is known about intracellular phosphate metabolism, and it has not been possible to correlate intracellular phosphate levels, and subsequent changes in phosphate metabolism, with increased tumor cell proliferation. To elucidate whether a scenario of "phosphate addiction" exists, the development of new tools is sorely needed, and is the goal of the current proposal. Using an interdisciplinary approach that combines synthetic chemistry with cell biology and metabolomics, our lab is addressing this hypothesis in the context of bone metastasis. We are developing small-molecule fluorescent phosphate sensors to measure phosphate release during osteolysis and phosphate uptake in adjacent metastatic breast cancer cells. In addition, we are determining how the metabolic network of these cells handles the phosphate surplus in the bone microenvironment. Applying newly developed capture reagents from our lab to enrich for the phospho-metabolome, in combination with global metabolomics, will provide a wealth of information on phosphate-dependent metabolic rewiring. Overall, we hope to change the way phosphate is viewed: Instead of considering phosphate as a passive building block, it should be recognized as an active regulator of cellular metabolism and behavior. Understanding the metabolic requirements for successful colonization can lead to the development of effective therapies for patients with already-established metastases. These therapies are critically needed, as tumors are generally considered incurable once they have metastasized to bone.