BROWNING OF WHITE ADIPOSE CELLS BY INTERMEDIATE METABOLITES: AN ADAPTIVE MECHANISM TO TUMOR ENVIRONMENT

GANTOV M; PAGNOTTA P; RINDONE G; RIERA M; MERONI S; CALVO JC; TONEATTO J

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC).; 2019

SAIC

Abstract/Resumen: Interaction between epithelial cells and the adipose environment is a fundamental step in the regulation of tumor behavior in mammary cancer. It has been shown that adipocyte differentiation, browning and thermogenesis, contribute to lactate metabolism, leading to a Warburg effect. We, previously, demonstrated morphologic changes in adipocytes indirectly cocultured with breast cancer cells, suggesting a first step towards browning. We, now, suggest that soluble factors released by breast cancer cells impact adipose lactate metabolism by regulation of MCTs expression. We evaluated the effect of 72 h conditioned media (CMs) from a normal mouse mammary epithelial cells (NMuMG) and three mouse mammary cancer cell lines (LM3, 4T1 and MC4L1), as well as indirect coculture (IC, transwells) on UCP1 uncoupling protein, MCT4 lactate transporter expression (Western blot) and lactate release into the medium by 3T3-L1 adipocytes, compared to control adipocytes. Results obtained (times over control) showed that the cancer cell lines increased UCP1 (CMs: Control= 1, NMuMG=2.10, LM3= 2.14, 4T1= 5.05, MC4L1= 2.92; IC: Control= 1, NMuMG= 3.82, LM3= 2.12, 4T1= 4.19, MC4L1= 1.28), as well as MCT4 expression (CMs: Control= 1, NMuMG= 1.26, LM3= 1.33,4T1= 2.95, MC4L1= 2.56; IC: Control= 1, NMuMG= 2.25, LM3=0.86, 4T1= 2.30, MC4L1= 1.29). When lactate released into the culture medium, an increase was also observed with the cancer cell lines (CMs: Control= 1, LM3= 1.06, 4T1= 1.32; IC: Control=1, LM3= 2.43, 4T1= 4.08). In conclusion, taken together, these results clearly show the metabolic and phenotypic switch (browning) on 3T3-L1 adipocytes when presented to soluble factors secreted by mammary epithelial cancer cells. This could represent an adaptive mechanism to changes in the microenvironment.