Matthew L. Goodwin, M.D., Ph.D.

Assistant Professor
Orthopaedic Surgery
Spine Surgery

Molecular Cell Biology Program
Cancer Biology Program
Molecular Genetics and Genomics Program

  • matthewlgoodwin@wustl.edu

  • Metabolism of cancer, targeting tumor metabolism by blocking metabolic pathways

Research Abstract:

Our primary lab interest is on the role lactate transport plays in metabolism and more specifically,
tumorigenesis. The Goodwin lab is focused on targeting lactate transportation as a means of attacking
cancers. 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"), man๔€œ
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 transport 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. 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, one of our current
projects 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 appear to 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.

Selected Publications:

Glancy B, Kane DA, Kavazis AN, Goodwin ML, Willis WT, Gladden LB. Mitochondrial lactate metabolism: history and implications for exercise and disease. J Physiol. 2021 Feb 599(3):863-888.

Goodwin ML. Leading in a time of uncertainty: spine care during COVID-19. Spineline May/June 2020.

Goodwin ML, Gladden LB, Nijsten MWN. Lactate-Protected Hypoglycemia (LPH). Front Neurosci. 2020 Sep 3;14:920.

Stivers J and Goodwin ML. Spinal Manifestations and Surgical Management of Neurofibromatosis Type 1. Spineline March/April 2020.

Pennington Z, Lubelski D, Westbroek EM, Cottrill E, Ehresman J, Goodwin ML, Lo SF, Witham TF, Theodore N, Bydon A, Sciubba DM. Spinal cord float back is not an independent predictor of postoperative C5 palsy in patients undergoing posterior cervical decompression. Spine J. 2020 Feb 20(2):266-275.

Last Updated: 4/30/2021 6:08:39 PM

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