Poster Presentation 31st Lorne Cancer Conference 2019

Crosstalk between oncogenic signaling pathways reprograms lipid metabolism in cancer (#396)

Srimayee Vaidyanathan 1 , Kristin K Brown 1 2
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC, Australia

Cancer cells have unique energetic and biosynthetic demands that are fulfilled through the reprogramming of cell metabolism, thereby sustaining tumour progression. A frequently observed but poorly understood metabolic alteration occuring in cancer cells is the activation of de novo lipogenesis. Our work has focused on the oncogenic transcriptional co-activator YAP, a master regulator of organ size and tumourigenesis. Although YAP is known to be aberrantly activated in a number of human cancers, the mechanisms by which YAP promotes tumourigenesis are not well characterised. We find that YAP overexpression activates de novo lipogenesis in vitro. This occurs via YAP-induced transcriptional upregulation of serum- and glucocorticoid-regulated kinase 1 (SGK1), an effector of the oncogenic phosphoinositide 3-kinase (PI3K) pathway. Downstream of YAP, SGK1 promotes mTORC1 signalling, which in turn activates the master regulators of lipogenesis, sterol regulatory element-binding proteins 1/2 (SREBP1/2). Notably, we observe that inhibition of key enzymes involved in the de novo lipogenesis pathway blocks hyperproliferation associated with YAP-driven transformation. Our data reveal an important mechanism of crosstalk between two key oncogenic signaling pathways, highlighting a metabolic vulnerability that may be exploited in order to disrupt oncogenic YAP/PI3K activity.