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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2CA186753-01
Application #
8567164
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (56))
Program Officer
Mohla, Suresh
Project Start
2013-09-30
Project End
2018-08-31
Budget Start
2013-09-30
Budget End
2018-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$2,427,500
Indirect Cost
$927,500
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Hager, Anastasia; Wu, Mingxuan; Wang, Huanchen et al. (2016) Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues. Chemistry 22:12406-14
Yates, Lisa M; Fiedler, Dorothea (2016) A Stable Pyrophosphoserine Analog for Incorporation into Peptides and Proteins. ACS Chem Biol 11:1066-73
Williams, Florence J; Fiedler, Dorothea (2015) A Fluorescent Sensor and Gel Stain for Detection of Pyrophosphorylated Proteins. ACS Chem Biol 10:1958-63
Conway, John H; Fiedler, Dorothea (2015) An affinity reagent for the recognition of pyrophosphorylated peptides. Angew Chem Int Ed Engl 54:3941-5
Yates, Lisa M; Fiedler, Dorothea (2015) Establishing the stability and reversibility of protein pyrophosphorylation with synthetic peptides. Chembiochem 16:415-23