Obesity and melanoma metastasisUnderstanding the relevance of the adipose tissue as pre-metastatic niche in melanoma

Resumo

Increasing evidence support a link between obesity and tumor progression of various types of cancer. In melanoma, although controversial, studies in murine models and epidemiological data point to a positive correlation between obesity and melanoma incidence and progression. However, the implication of obesity in metastasis and the mechanisms underlying this association remain largely unexplored. Tumor microenvironment and pre-metastatic niche formation are two key processes governing metastasis. In this sense, in this thesis we tried to shed light on the underlying mechanisms linking obesity and melanoma metastasis, focusing on the study of the generation of novel pre-metastatic niches in the obese adipose tissue that we named “obese niches”. Here we show that HFD increases metastasis of the low metastatic B16-F1 melanoma model in retroperitoneal, epidydimal and inguinal fat tissue while this influence was not observed using the high metastatic B16-F10 model. Analysis of the factors involved shows that HFD induces the hypersecretion of different molecules in the retroperitoneal adipose tissue such as CCL6 that could be involved in melanoma metastasis. However, the analysis of CCL6 revealed that it does not have a direct role attracting melanoma cells. Our data support instead, that it may have an indirect role contributing to macrophage recruitment altering the tumor microenvironment. We observed an increased recruitment of macrophages in the adipose tissue of HFD-fed mice with expression of genes associated with an M2 phenotype such as Il10, Il1rn and Arg1. Finally, co-culture of B16-F1 melanoma cells with adipose tissue from HFD-fed mice, induced the expression of fibronectin and galectin 3 in melanoma cells and alters MAPK and STAT3 signaling pathways. Overall, our data suggest that the adipose tissue from HFD-fed mice favors B16-F1 metastasis and promotes the expression of pro-metastatic and pro-survival genes such as Fn1 or Lgals3. Although the mechanism involved in tumor cells homing to the adipose tissue needs further investigation, the increase secretion of cytokines such as CCL6 suggest the recruitment of M2 macrophages that could induce the formation of novel “obese niches” and favor melanoma metastasis