RNA-Seq to decipher breast cancer-adipocytes reciprocal reprogramming: evaluating the impact of glucose

The tumor microenvironment, including adipocytes, is a critical element for breast cancer (BC) progression, also responding to metabolic stimuli characterizing obesity and/or diabetes. The reciprocal reprogramming established between BC cells and adipocytes remains to be deciphered. We investigated (i) the effect of mammary adipocytes on BC cells and vice versa, (ii) the impact of glucose on BC cells, adipocytes and (iii) the impact of glucose on their cross-talk. We have identified adipocyte-modulated genes in BC cells and BC cell-modulated genes in adipocytes, dependently and independently of glucose levels. We identified the adipogenesis process as the most relevantly differentially regulated pathway both in cancer cells and in adipocytes upon exposure to high glucose concentration. Specifically, we observed that BC cells promote de-differentiation of adipocytes and re-shaping toward a fibroblast-like phenotype, particularly upon glucose lowering; the de-lipidation of adipocytes is paralleled by induction of adipogenesis genes in BC cells. To this end, we used a co-culture system in which mammary adipocytes and MCF7 BC cells were separated by an insert to allow the diffusion of soluble factors. Through RNA-Sequencing, the transcriptome of both cell types was determined, in co-cultures as well as a mono-cultures, while exposed to glucose concentrations resembling hyperglycemia or normoglycemia in humans. We obtained evidence that adipocytes and BC cells reciprocally modify their transcriptome.