Obesity Induces Temporally Regulated Alterations in the extracellular matrix that drive breast tumor invasion and metastasis.

ABSTRACT

Obesity is associated with increased incidence and metastasis of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype. The extracellular matrix (ECM) is a major component of the tumor microenvironment that drives metastasis. To characterize the temporal effects of age and high-fat diet-driven weight gain on the ECM, we injected allograft tumor cells at 4-week intervals into mammary fat pads of mice fed a control or high-fat diet (HFD), assessing tumor growth and metastasis and evaluating the ECM composition of the mammary fat pads, lungs, and livers. Tumor growth was increased in obese mice after 12 weeks on the HFD. Liver metastasis increased in obese mice only at 4 weeks, and elevated body weight correlated with increased metastasis to the lungs but not the liver. Whole decellularized ECM coupled with proteomics indicated that early stages of obesity were sufficient to induce changes in the ECM composition. Obesity led to increased abundance of the pro-invasive ECM proteins collagen IV and collagen VI in the mammary glands and enhanced the invasive capacity of cancer cells. Cells of stromal vascular fraction and adipose stem and progenitor cells were primarily responsible for secreting collagen IV and VI, not adipocytes. Longer exposure to HFD increased the invasive potential of ECM isolated from lung and liver, with significant changes in ECM composition found in the liver with short-term HFD exposure. Together, this data suggests that changes in the breast, lung, and liver ECM underlie some of the effects of obesity on TNBC incidence and metastasis.