Supplementary Figure S1. Coculture with preadipocytes has no effect on cancer cell invasion and coculture with mature adipocytes has no effect on prostate cancer cell number. Supplementary Figure S2. Adrenergic receptors do not control adipocyte lipolysis in response to tumor cell secretions. Supplementary Figure S3. The metabolic remodeling towards uncoupled FAO observed in cocultivated cells is not involved in the increase in prostate cancer invasion induced by adipocytes. Supplementary Figure S4. ROS positively regulate prostate cancer cells invasion. Supplementary Figure S5. 10mM NAC and 10μM DPI do not affect PC3 viability. Supplementary Figure S6. Coculture and palmitate stimulate tumor invasion through NOX in Du-145 cells. Supplementary Figure S7. NOX5 invalidation leads to a strong decrease in cell survival.
Funding
Inserm, Cancer Research Center of Toulouse
French National Cancer Institute
French Association against Muscular Dystrophies
ARTICLE ABSTRACT
Prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is increasingly believed to play a paracrine role in prostate cancer progression. Our previous work demonstrates that adipocytes promote homing of prostate cancer cells to PPAT and that this effect is upregulated by obesity. Here, we show that once tumor cells have invaded PPAT (mimicked by an in vitro model of coculture), they establish a bidirectional crosstalk with adipocytes, which promotes tumor cell invasion. Indeed, tumor cells induce adipocyte lipolysis and the free fatty acids (FFA) released are taken up and stored by tumor cells. Incubation with exogenous lipids also stimulates tumor cell invasion, underlining the importance of lipid transfer in prostate cancer aggressiveness. Transferred FFAs (after coculture or exogenous lipid treatment) stimulate the expression of one isoform of the pro-oxidant enzyme NADPH oxidase, NOX5. NOX5 increases intracellular reactive oxygen species (ROS) that, in turn, activate a HIF1/MMP14 pathway, which is responsible for the increased tumor cell invasion. In obesity, tumor-surrounding adipocytes are more prone to activate the depicted signaling pathway and to induce tumor invasion. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results.
Our work emphasizes the key role of adjacent PPAT in prostate cancer dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.
