Mitochondrial Fission Induces Glycolytic Reprogramming in Cancer-Associated Myofibroblasts, Driving Stromal Lactate Production, and Early Tumor Growth

Abstract

Recent studies have suggested that cancer cells behave as metabolic parasites, by inducing oxidative stress in adjacent normal fibroblasts. More specifically, oncogenic mutations in cancer cells lead to ROS production and the “secretion” of hydrogen peroxide species. Oxidative stress in stromal fibroblasts then induces their metabolic conversion into cancer-associated fibroblasts. Such oxidative stress drives the onset of autophagy, mitophagy, and aerobic glycolysis in fibroblasts, resulting in the local production of high-energy mitochondrial fuels (such as L-lactate, ketone bodies, and glutamine). These recycled nutrients are then transferred to cancer cells, where they are efficiently burned via oxidative mitochondrial metabolism (OXPHOS). We have termed this new energy-transfer mechanism “Two-Compartment Tumor Metabolism”, to reflect that the production and consumption of nutrients (L-lactate and other catabolites) is highly compartmentalized. Thus, high-energy onco-catabolites are produced by the tumor stroma.

Here, we used a genetic approach to stringently test this energy-transfer hypothesis. First, we generated hTERT-immortalized fibroblasts which were genetically re-programmed towards catabolic metabolism. Metabolic re-programming towards glycolytic metabolism was achieved by the recombinant over-expression of MFF (mitochondrial fission factor). MFF over-expression results in extensive mitochondrial fragmentation, driving mitochondrial dysfunction. Our results directly show that MFF-fibroblasts undergo oxidative stress, with increased ROS production, and the onset of autophagy and mitophagy, both catabolic processes. Mechanistically, oxidative stress induces autophagy via NF-kB activation, also providing a link with inflammation. As a consequence MFF-fibroblasts showed intracellular ATP depletion and the extracellular secretion of L-lactate, a critical onco-catabolite. MFF-fibroblasts also showed signs of myofibroblast differentiation, with the expression of SMA and calponin.

Importantly, MFF-fibroblasts signficantly promoted early tumor growth (up to 6.5-fold), despite a 20% overall reduction in angiogenesis. Thus, catabolic metabolism in cancer-associated fibroblasts may be a critical event during tumor intiation, allowing accelerated tumor growth, especially prior to the onset of neo-angiogenesis.