METABOLIC COOPERATION BETWEEN PREADIPOCYTES AND BREAST TUMOR CELLS: ROLE OF EXTRACELLULAR VESICLES IN OBESITY

INTRODUCTION AND OBJECTIVE: Obesity is a known risk factor for breast cancer, but the mechanisms remain unknown. In this scenario, despite being neglected, preadipocytes plays a role Therefore, the present work aimed i. to build an in vitro model to produce extracellular vesicles (EV) derived from obese (PEV OB) and eutrophic (PEV EUT) preadipocytes and ii. to investigate the functional and metabolic changes undergone by MDA-MB-231 breast cancer cells when stimulated with those EV.

METHODOLOGY: Primary human preadipocytes were educated with the secretome released by the subcutaneous  AT biopsies obtained from obese or eutrophic individuals (CAAE:36880914.0.0000.5259). After education, the PEV were isolated by centrifugation (20.000 x g). MDA-MB-231 cells were treated with PEV OB or PEV EUT in the presence or absence of Etomoxir (ETO) or 2-deoxy-d-glucose (2-DG). Migration assays were accessed by Wound healing; metabolic parameters such as  L-lactate and  ATP levels and glucose-6-phosphate dehydrogenase (G6PDH) and pyruvate kinase (PK) activity were accessed by colorimetric commercial kits (Sigma). Statistical analysis was performed using one-way ANOVA with Sidak's post-tests and a value of p < 0.05 was considered.

RESULTS AND DISCUSSION: PEV OB increased cell migration by 3-fold compared to untreated MDA-MB-231 cells and 1.8-fold compared to MDA-MB-231 cells treated with PEV EUT and in the presence of ETO, cell migration induced by PEV OB and PEV EUT decreased by 2.3-fold and 1.5-fold, respectively. PEV EUT increased total L-lactate levels compared to untreated cells and PEV OB. Notably, in the presence of ETO, PEV OB increased lactate production and reduced G6PDH activity.

CONCLUSION: PEV EUT favors glycolytic metabolism meanwhile PEV OB favors oxidative metabolism. Moreover, PEV EUT and PEV OB increase migratory capacity to a different extent mainly due to  the metabolic shift undergone  in MDA-MB-231 cells in both conditions.
FUNDING: CAPES, CNPq, and FAPERJ