UCLA

Obesity in the United States is a problem of epidemic proportions. The CDC suggests that around 40% of adults and 20% of children are obese, and these numbers show no signs of tapering off. In the last few decades, it has been established that in addition to many well-known cardiometabolic complications, increased adiposity also plays a role in cancer—forming a synergistic relationship with cancer cells resulting in more aggressive, difficult to treat disease. Compelling evidence has been presented supporting the negative impact of obesity in numerous cancers, namely pointing toward mechanisms related to lipid metabolism and increased inflammation resulting from aberrations in adipose tissue. One caveat to the bulk of obesity and cancer research is the focus on solid tumor cancers occurring in adults, thus failing to account for juvenile and hematological malignancies such as pediatric acute lymphoblastic leukemia (ALL)–the most common childhood cancer. Additionally, adipose tissue is notoriously difficult to culture ex vivo, resulting in frequent use of artificial in vitro adipocyte models and animal models that limit translational application. To address shortcomings in adipose culture methods, we developed a novel culture method using polydimethylsiloxane (PDMS) flow chambers, allowing us to more effectively culture whole patient adipose tissue ex vivo. To investigate the crosstalk between adipose tissue and acute lymphoblastic leukemia, we conducted single-cell RNA sequencing of epididymal adipose tissue in a syngeneic obese mouse model of juvenile ALL. Results show that PDMS flow chambers are a promising alternative to current methods used to study adipose tissue, as they maintain tissue viability, functionality, and better simulate adipose tissue in vivo since 3D structure and stromal cell network are retained. Our exploration of adipose tissue-ALL crosstalk at the single-cell resolution revealed a novel mechanism by which Prostaglandin E2 released from adipose tissue binds leukemia cells and increases expression of Receptor Activator of Nuclear Factor Kappa- beta Ligand (RANKL), which is associated with bone breakdown and central nervous system metastasis. Collectively, our findings help improve on current adipose tissue culture methods and provide novel insight into how the obese adipose tissue microenvironment plays a role in promoting cancer progression.