our science
The lab’s goal is to understand how immunity and cancer is fueled. In the Puleston Lab, we believe that by turning our attention to cellular metabolism, we can decode key underlying principles of immune & tumor cell biology. Most importantly, by investigating the intersection of metabolism, cancer, and the immune system, we hope to expose novel metabolic vulnerabilities that can be utilized for disease prevention and therapy. The lab's focus spans three themes: 1. To decipher the metabolic factors that govern immune cell function; 2. To decode metabolic control of tumor growth, metastasis and anti-tumor immunity; 3. To explore the cellular metabolism of human cancer and immunity in situ.
metabolic governance of immunity
Cellular metabolism potently regulates the acquisition of specific effector functions in immune cells. This understanding has been delineated across a body of work that often applies in vitro experimentation as a proxy for in vivo cellular metabolism. However, the metabolic activity of cells actively occupying the tissue, where they perform their conical functions, is still largely unknown. We apply cutting-edge techniques such as in vivo metabolic tracer infusion and state-of-the-art mass spectometry to understand how metabolism directs immunity inside tissues. We are particularly focussed on understanding how the local tissue and tumor environment orchestrates the acquisition of niche-specific phenotypes and functions following immune cell entry from the blood.
Understanding cancer metabolism
Cancer is one of the leading causes of mortality and morbidity worldwide. Tumour initiation and progression requires the metabolic reprogramming of cancer cells. Exploring this remodeling is key to revealing how tumors fuel their growth. We strive to understand how cancer driver mutations and environmental nutrient availability direct the ways in which tumor cells rewire their metabolism. By distinguishing these active metabolic nodes, we hope to identify metabolic vulnerabilities that may be targeted therapeutically to limit tumor growth. As part of this endeavor, we also examine the metabolic cross-talk between cancer and immune cells. Tumor cells are adept at re-shaping the local environment to limit immune cell function. We scrutinize how this occurs and how specific therapeutic interventions transform the tumor microenvironment to favor anti-tumor immunity and restrict cancer growth.
Exploring human metabolism in situ
Understanding the biology of human cells whilst they reside in their natural environment - the tissues, is challenging. This is underwritten by pertinent ethical and experimental boundaries that constrain our ability to access and examine cells within living human organs. As a result, much of what we know about human biology and disease is derived from in vitro studies or animal systems. This is also true in regards to the investigation of cancer and tumor metabolism. Endeavors to understand human cellular metabolism in situ is restricted by several technical and logistical barriers, the most prominent being the need to infuse metabolic tracers (e.g., 13C glucose). The use of such tracers is imperative to understand cellular metabolic activity. These tools allow us to “trace” the flow of “heavy” atoms throughout the metabolome by mass spectrometry (MS), providing insight into nutrient utilization and the metabolic activity of distinct pathways. Therefore, to investigate cellular metabolism in vivo requires infusing metabolic tracers into living organisms. In humans, routine use of these tracers remains limited. In our lab, we are exploring innovative new ways to explore cancer metabolism in humans. These include the infusion of 13C isotopologues into patients. In another approach, in close partnership with Dr. Zeeshan Akhtar, we have developed methods to keep intact, tumor-bearing organs alive outside of the body - a system that now allows us to access, perturb, and investigate the biology and metabolism of cancer and immune cells whilst they reside within their native environment - the tumor.
