Altered metabolism is an established hallmark of cancer, with recent research focus on lipid metabolism. Apart from being essential components of cell membranes that are replicated during proliferation, and as cellular energy storage, cellular lipid composition is critical for the regulation of structural organization at organelle and membrane microdomain levels as well as signal transduction. We applied integrative multiomics approach to discover lipid and glycosphingolipid changes in oesophageal adenocarcinoma and triple negative breast cancer, respectively.
In the first project, concurrent tissue lipidomic and proteomic analyses of oesophageal biopsies revealed increased polyunsaturated fatty acids. Elevated lipid desaturases FADS1, FADS2 and DEGS1 were discovered by orthogonal transcriptomic and validated by immunohistochemistry analyses. Furthermore, we also observed an increase in multiple redox proteins and transcripts. These results suggest an adaptive antioxidative response associated with gastro-esophageal reflux disease-induced inflammation and oxidative stress, which causes peroxidation of the increased polyunsaturated lipids.
The second project began with a bioinformatics interrogation of public transcriptomic data for triple negative breast cancer (TNBC), identifying lacto/neo-lacto glycosphingolipids (GSL) and the enzyme B3GNT5 to be a candidate therapeutic target. We generated B3GNT5 knockout, and restored TNBC cell lines MDA-MB436 and BT549 for functional and molecular characterization. Loss lacto/neo-lacto GSL was observed in B3GNT5 KO cells, which exhibited impaired cell adhesion and migration. Unexpectedly, B3GNT5 KO/rescue also led to the loss/rescue of the ganglioside GM1 in both cell lines. As GM1 is implicated in lipid raft formation and cell adhesion, we are now investigating lipid raft amount, protein composition and function as a mechanism underpinning B3GNT5-dependent cell adhesion.
Together, these two projects illustrate the utility of integrative multiomics to unveil complex mechanisms.