Alterations in membrane lipids as an adaptive response to high intratumoral pressure: a novel ubiquitous therapeutic target

The development and progression of cancer is accompanied by numerous molecular changes, not only at the level of the DNA, but also in other classes of molecules such as lipids. Recent lipidomics analysis has revealed dramatic changes in lipids in tumor cells compared to their normal counterparts. Among the most dramatic and recurrent changes are the increases in chain length and mono-unsaturation of fatty acyl chains in phospholipids. These changes have been associated with the aberrant activation of de nova lipogenesis and an altered fatty acid metabolism that is found in the majority of tumors of many different types. This process is linked to the Warburg effect and in part involves the synthesis of saturated fatty acids mainly of 16 carbons from simple substrates such als glucose and glutamine, followed by mono-unsaturation and chain elongation by dedicated enzymes such as fatty acid elongase (ELOVL) and desaturates (SCD, FADS) which also work on diet-derived fatty acids. It is generally assumed that activation of these pathways is important as feedstock of lipid substrates for membrane synthesis to support rapid cell proliferation of cancer cells. By changing membrane lipid composition, these pathways also protect cancer cells from oxidative stress, lipotoxity and therapeutic insults. Other than that, the role of these dramatic changes in membrane lipid composition remains enigmatic. In this project we aim to better understand the role of the increased acyl chain length and mono-unsaturation in tumors and to establish this process as a novel angle for therapeutic intervention. In doing so, we want to explore a completely novel concept in which the observed changes in membrane lipid compositions play an important adaptive role in the protection of cancer cells from the increased interstitial and solid pressure that is observed in many tumors and is considered a fundamental feature of cancer biology.