Cholesterol remodels the endoplasmic reticulum to control myofibroblastic CAF function

Abstract

Chronic exposure of local fibroblasts to the reactive tumour niche results in the emergence of cancer-associated fibroblasts (CAFs), which can be classed into multiple subtypes with distinct functional and molecular characteristics. Of these subtypes, myofibroblastic CAFs (myCAFs), contribute to tumour progression primarily by depositing and remodelling extracellular matrix (ECM) within the tumour microenvironment (TME). ECM production is known to be a metabolically demanding process, but specific metabolic pathways that are reprogrammed during myCAF activation are poorly understood. Here, we show that cholesterol biosynthesis is elevated in myCAFs relative to normal fibroblasts. We find that cholesterol is specifically enriched in the myCAF endoplasmic reticulum (ER) membrane and is associated with augmented ER mass and enhanced ER secretory function. Importantly, we demonstrate that pharmacological or genetic inhibition of cholesterol biosynthesis plays a critical role in regulating the ECM-secreting and ECM remodelling function of myCAFs. Moreover, we show that inhibition of cholesterol biosynthesis in myCAFs markedly constrains mammary tumour metastasis in vivo. These studies suggest that cholesterol biosynthesis represents a metabolic vulnerability that can be exploited to normalise myCAF-mediated ECM dysfunction in the TME.