We have two focus areas in the lab. The first investigates the mechanisms by which obesity influences cancer biology and response to treatment. The second examines how adipose tissue responds to radiation to influence metabolic health and immune function in cancer patients. In both areas there is a current emphasis on the role of macrophages in adipose tissue and tumors, although we also pursue obesity-induced metabolic changes in other cell types.
Area I: Influence of obesity on cancer biology and response to treatment
Obesity now affects close to half of adults in the US and is associated with the metabolic syndrome, dysfunctional adipose tissue, a unique cancer risk profile, and increased cancer mortality. Our mechanistic understanding of how obesity impacts cancer outcomes remains limited, as are therapeutic options that account for the unique metabolic pathophysiology found in obese patients. This lack of personalization represents a major unmet clinical need that calls for better understanding of the underlying molecular and cellular mechanisms influencing cancer behavior in obese patients.
Obesity is marked by an expansion of adipose tissue that is often characterized by dysfunctional inflammation and an increased number of macrophages infiltrating the tissue. Macrophages also play diverse pro-tumorigenic roles, including promoting cancer cell proliferation and invasion, inducing angiogenesis, and suppressing anti-tumor immunity. They preferentially engage specific metabolic pathways to perform these functions, such as glycolysis during the promotion of angiogenesis. As obesity rewires cellular metabolism throughout the body, macrophages in both the adipose and tumor compartments are expected to adopt different metabolic and functional profiles as a result, which in turn can promote more aggressive cancer behavior and explain the worse outcomes that obese breast cancer patients experience (Fig. 1). The intimate link between macrophage metabolism and function represents a unique therapeutic opportunity in obesity-driven breast cancer.
Projects in this area include:
- Profiling macrophage metabolism and functional profiles in tumors and adjacent adipose tissue to discover targetable vulnerabilities that promote tumor growth
- Mining electronic health records for improved metrics of obesity and metabolic dysfunction in cancer patients to discern more precise links between metabolic physiology and cancer outcomes
Area II: Response of adipose tissue to radiation—Metabolism, Immunity, and Aging
Ionizing radiation is a key component of definitive treatment for many malignancies. Therapeutic doses of radiation are constrained by the ability of normal tissue to maintain or recover their function after exposure. While these thresholds have been well established for most normal tissue types through decades of empirical experience, little is known about the response of adipose tissue to radiation in humans.
Once thought to be an inert lipid depot, adipose tissue is now recognized as an endocrine organ that secretes hormones, known as adipokines, that influence systemic metabolic physiology. Maladaptive remodeling of adipose tissue from insults such as chronic caloric excess has been shown to contribute to the development of insulin resistance. Adipose tissue also hosts a dynamic and diverse immune cell population, whose functions are an active area of investigation. Finally, intriguing studies in the field of senescence have shown that irradiated preadipocytes from adipose tissue can induce accelerated whole organismal aging.
We previously reported that adult survivors of childhood cancer who received abdominal radiation as children, either targeted or as part of total body irradiation, exhibit signs of metabolic dysfunction such as elevated HbA1c, lower HDL/LDL ratio, and an altered adipokine profile associated with increased insulin resistance and systemic inflammation (JCI Insight, 6(21): e153586). This phenotype occurs at normal body weights, unlike in the general population where the main risk factor for insulin resistance is obesity. We also uncovered evidence for an expansion of TREM2+ macrophages in the abdominal subcutaneous adipose tissue of survivors who received abdominal radiation (Fig. 2).
Projects in this area include:
- Determining the extent of adipose tissue radiation exposure in adult patients undergoing routine abdominal/pelvic irradiation as part of cancer treatment
- Determining the metabolic health consequences of such exposure
- Developing a mouse model of adipose irradiation that recapitulates metabolic and immune changes observed in human patients who receive radiation to the abdominal adipose depots