Global lipid remodelling by hypoxia aggravates migratory potential in pancreatic cancer while maintaining plasma membrane homeostasis

Abstract

Hypoxia plays an important role in pancreatic cancer progression. It drives various metabolic reprogramming in cells including that of lipids, which in turn, can modify the structure and function of cell membranes. Homeostatic adaptation of membranes is well-recognized, but how and if it is regulated in hypoxic pancreatic cancer and its relation to aggressive phenotype and metastasis remains elusive. Here we show hypoxia-induced extensive global lipid remodelling spanning changes in lipid classes, unsaturation levels, glyceryl backbone and acyl chain lengths. No major modulation of plasma membrane biophysical properties revealed a decoupling of lipidome modulation from membrane properties under hypoxia. This was supported by observing minor changes in the lipidome of plasma membranes under hypoxia. Further, hypoxia increased migration and invasion underpinned by reduced actin volume, cell cortical stiffness and facile tether dynamics. In conclusion, we demonstrate buffering of the lipidome alterations leading to a homeostatic membrane response. These findings will help to understand the hypoxic regulation of pancreatic membrane homeostasis and identify tangible theranostic avenues.

Keywords: Cell membranes; Hypoxia; Lipidomics; Membrane biophysics; Pancreatic cancer.