Compartment-specific activation of PPAR governs breast cancer tumor growth, via metabolic reprogramming and symbiosis

The role of PPAR in cancer therapy is controversial, with studies showing either pro-tumorigenic or antineoplastic effects. This debate is very clinically relevant, because PPAR agonists are used as antidiabetic drugs. Here, we evaluated if the effects of PPAR on tumorigenesis are determined by the cell type in which PPAR is activated. Second, we examined if the metabolic changes induced by PPAR, such as glycolysis and autophagy, play any role in the tumorigenic process. To this end, PPAR was overexpressed in breast cancer cells or in stromal cells. PPAR-overexpressing cells were examined with respect to (1) their tumorigenic potential, using xenograft models, and (2) regarding their metabolic features. In xenograft models, we show that when PPAR is activated in cancer cells, tumor growth is inhibited by 40%. However, when PPAR is activated in stromal cells, the growth of co-injected breast cancer cells is enhanced by 60%. Thus, the effect(s) of PPAR on tumorigenesis are dependent on the cell compartment in which PPAR is activated. Mechanistically, stromal cells with activated PPAR display metabolic features of cancer-associated fibroblasts, with increased autophagy, glycolysis and senescence. Indeed, fibroblasts overexpressing PPAR show increased expression of autophagic markers, increased numbers of acidic autophagic vacuoles, increased production of L-lactate, cell hypertrophy and mitochondrial dysfunction. In addition, PPAR fibroblasts show increased expression of CDKs (p16/p21) and -galactosidase, which are markers of cell cycle arrest and senescence. Finally, PPAR induces the activation of the two major transcription factors that promote autophagy and glycolysis, i.e., HIF-1 and NFB, in stromal cells. Thus, PPAR activation in stromal cells results in the formation of a catabolic pro-inflammatory microenvironment that metabolically supports cancer growth. Interestingly, the tumor inhibition observed when PPAR is expressed in epithelial cancer cells is also associated with increased autophagy, suggesting that activation of an autophagic program has both pro- or antitumorigenic effects depending on the cell compartment in which it occurs. Finally, when PPAR is expressed in epithelial cancer cells, the suppression of tumor growth is associated with a modest inhibition of angiogenesis. In conclusion, these data support the two-compartment tumor metabolism model, which proposes that metabolic coupling exists between catabolic stromal cells and oxidative cancer cells. Cancer cells induce autophagy, glycolysis and senescence in stromal cells. In return, stromal cells generate onco-metabolites and mitochondrial fuels (L-lactate, ketones, glutamine/aminoacids and fatty acids) that are used by cancer cells to enhance their tumorigenic potential. Thus, as researchers design new therapies, they must be conscious that cancer is not a cell-autonomous disease, but rather a tumor is an ecosystem of many different cell types, which engage in metabolic symbiosis.