Matthew Goodwin

Cancer cells hold particular interest because of their unique metabolic history. Once described as unique because they were “lactate-producing” even when oxygen was plentiful (the “Warburg Effect”), many cancer cells have since been described as “lactate-consuming” (or “reverse Warburg”). The current debate as to whether a cancer cell produces lactate or consumes lactate as a fuel is further confounded by the confusion that has surrounded lactate metabolism in many medical specialties.

Once thought of as a metabolic waste product, lactate is now known to be a valuable and efficient fuel that can be transported and used throughout the body. In fact, lactate is preferred over glucose by most tissues. In contrast to glucose, lactate can move in and out of cells throughout the body via the ubiquitously expressed monocarboxylate transporters (MCTs). This is important because skeletal muscle and liver both store glucose as glycogen. While the liver can release glucose from glycogen into the blood, skeletal muscle is unable to do so. However, muscle is equipped with receptors that bind catecholamines and lead to the breakdown of glycogen to lactate, which is then driven by diffusion down its concentration gradient to the blood, where it can circulate to tissues in need. Thus, substrate from muscle throughout the body can be quickly and efficiently mobilized in times of need. Lactate enters cells, is converted to pyruvate, and is oxidized in the mitochondria. This robust and flexible system of substrate shuttling makes lactate the ideal system for tumor cells to hijack.

Tumors of all types certainly appear to rely on lactate to some degree. In some cases they appear to be using lactate as a fuel (Goodwin et al., Cancer Cell 2014), while in other instances they appear to be producing lactate. Note that evidence for both exists (depending on the tumor type and condition) and that inhibiting lactate transport seems to have an effect on tumors in both situations. Note that for some cancers, evidence exists that they do both! This discrepancy is mainly due to the profound influence the tumor microenvironment has on tumor cell behavior, and the difficulty in replicating the tumor microenvironment in the lab.

To that end, our lab focuses on defining the metabolic behavior of a tumor cell by a variety of methods and unique laboratory techniques, and then targeting that unique behavior. For example, current work is examining the role of MCTs in osteosarcoma metabolism. For many years tumor treatment was limited to radiation, chemotherapy, and surgery. We have now entered the era of targeted treatments, and targeting tumor metabolism holds the potential for new, more effective, and less toxic cancer treatments.

A secondary interest of the lab is the role of lactate in intervertebral disc (IVD) metabolism and degenerative disc disease. IVDs and tumors represents the “extremes” of metabolism. Tumors are often hyper-vascular, while discs are largely avascular. This contrasting metabolic behavior represents opposing ends of the spectrum of human tissue, providing a unique insight into basic principles underlying metabolism. However, disc behavior also mirrors tumor behavior in many ways. The nucleus pulposus represents a relatively avascular core at the center of a complex 3D microenvironment. Given this, IVDs function much the way tumors do, by relying on lactate shuttling to coordinate metabolism. Early work has shown that inhibiting MCTs in discs leads to rapid IVD degeneration. By studying the role of lactate as a nutrient in disc metabolism and the complicated IVD microenvironment, we are able to move closer to treatments for many cancers and many spinal pathologies, conditions that affect millions of people.