Cancer metastasis is often associated with poor prognosis. Obesity increases the risk of metastasis, yet despite the rising prevalence of overweight and obese adults (about 39%) and children (over 18%) worldwide, we lack significant knowledge about how obesity drives cancer progression and metastasis. Breast cancer is of particular interest in the context of obesity, as the majority of the breast microenvironment consists of adipose (fat) tissue.
Kirsty Spalding and her group have produced preliminary data showing that adipocytes in obese patients without cancer secrete pro-oncogenic factors that promote metastasis. This suggests that adipocytes distal to the cancer site can affect cancer cell behavior. In addition, the group has identified a subset of adipocytes that undergo premature senescence in response to obesity and hyperinsulinemia. Failing to clear such cells may lead to a microenvironment that nurtures cancer cell invasion, migration and metastasis.
With this ASPIRE Award, Spalding and her group aim to compare and characterize the pro-oncogenic factors secreted by adipocytes in lean and obese individuals; to identify which factors promote metastasis in breast cancer; to determine whether adipocyte senescence promotes cancer cell invasiveness; and to determine whether clearing such cells improves outcomes for breast cancer patients. The team has already determined that the type 2 diabetes drug metformin blocks adipocyte cell cycle entry, thereby preventing senescence and formation of a pro-cancer phenotype. They will now investigate whether other drugs known as senolytics (drugs that selectively clear senescent cells) can also prevent the formation of a pro-cancer phenotype by reducing the senescent cell burden. Importantly, they will use primary human adipocytes, utilizing the lab’s expertise to study this system in a more translationally relevant manner than has been done in previous studies. Insights gained from this project may also further our understanding of how adipocytes contribute to other cancers strongly associated with obesity.