Lipidomic Dynamics of Ovarian Cancer in Dicer-Pten Double-Knockout (DKO) Mouse Model
Ovarian cancer (OC) is responsible for more deaths than any other cancer associated with the female reproductive system. In addition, it is the fifth leading cause of cancer-related death in women. This is particularly the case because of the low survival rate associated with late diagnosis coupled with nonspecific symptoms at early stages. Particularly deadly is the High-grade serous carcinoma (HGSC), which doubles as the most frequent type of OC. An HGSC mouse model Dicer-Pten Double-Knockout (DKO), was used to study the dynamics of lipidomic changes in this disease. DKO mouse mimics many features of the human disease. For example, it originates in the fallopian tube before spreading to the ovary and the abdominal cavity. After two months of breeding, serum samples of DKO and DKO control mice were collected every two weeks for six months. Ultra-high performance liquid chromatography−mass spectrometry (UHPLC−MS) was used for serum lipidomic profiling. To unpack the dynamics of lipidomic changes we applied univariate statistical methods for observing differences between the two groups, hierarchical clustering analysis was used to reveal the clustering of lipidomic trajectories overtime. Furthermore, supervised machine learning algorithms was used for a time-resolved DKO classification, an approach critical for discovering potential early stage biomarker candidates. Finally, survival analysis methods were used for the discovery of potential circulating lipid prognostics. In summary, preliminary results shows thataltered lipidomic levels are reported in fatty acids (FA) and their derivatives, phospholipids, and sphingolipids. Early progression of OC is marked by primarily increased levels of phosphatidylcholine and phosphatidylethanolamine. In contrast, later stages were marked by more diversified lipids alterations, including FA and FA derivatives, triglyceride, ceramide, hexosylceramides, sphingomyelin, lysophosphatidylcholine, and phosphatidylinositol. These alterations provide evidence of perturbations in cell membrane stability, cellular proliferation, and survival.
