Understanding phosphate metabolism in cancer and metastasis

描述（由申请人提供）：肿瘤细胞的代谢重组通常被认为是癌症的标志，人们普遍认为葡萄糖和谷氨酰胺代谢的改变驱动了癌细胞的增殖。我们假设类似的情况也存在于

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.