2017 Cardiovascular Research Day Abstract Book

4
Identification of a Lipid Signature in Clear Cell Renal Carcinoma (ccRCC) Suggest a Role of
Phosphatidylinositol Remodeling in Disease Progression
Chase Neumann 1 • Renliang Zhang, PhD 1 • Christopher Przybicin, MD 2 • Brian Rini, MD 3 •
Mark Brown, PhD 1
1Cellular and Molecular Medicine, Cleveland Clinic • 2 Robert J. Tomsich Pathology and Laboratory
Medicine, Cleveland Clinic • 3 Hematology and Oncology Taussig Cancer Institute, Cleveland Clinic
Graduate Student
The most lethal urological cancer and third most common urological cancer in the United States is
clear cell renal carcinoma (ccRCC). Approximately 64,000 individuals in the United States are
diagnosed with ccRCC annually, and more than 140,000 individuals die worldwide of ccRCC every
year. The “clear cell” characteristic of this deadly kidney cancer is due to abnormal deposition of
lipids in a large unilocular lipid droplet in cancer cells, and urinary biomarker studies have
identified lipid droplet-associated proteins as predictive markers of disease progression. However,
the mechanisms by which lipid metabolism impacts ccRCC progression are not well understood. We
hypothesized that a group of mitogenic lipids exist within the ccRCC microenvironment that
promote proliferation and metastatic potential. A high throughput Triple Time-of-Flight (TOF) LC-
MS/MS lipidomics screen of metastatic ccRCC tumor samples and matched non-tumor adjacent
tissue identifies a highly reproducible lipid signature of ccRCC. In agreement with previous reports,
cholesteryl esters are increased in the tumor vs non-tumor. We also found a striking increase in
phosphatidylinositol (PI) 36:4 and 34:1 in tumors. Membrane bound O-acyltransferase domain
containing 7 (MBOAT7) is a lysophosphatidylinositol (LPI) acyltransferase that preferentially
utilizes arachidonyl-CoA and 16:0 LPI as substrates. To further investigate the formation of 36:4 PI,
an MBOAT7 product, we used TCGA datasets to analyze stage-specific expression of MBOAT7.
MBOAT7 expression was found to increase with staging. This potential increase in
phosphatidylinositol production, coupled with decreases in known phosphatase activity like PTEN,
SACM1L, and MTM1 may lead to increased activation of the PI3K/Akt signaling activity. The impact
of this work may suggest mechanisms why some patients are refractory to PI3K/mTOR inhibitors,
while a small percentage (