Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4.

Authors

Ubaldo E. Martinez-Outshoorn, MD, Thomas Jefferson UniversityFollow
Joseph Curry, MD, Thomas Jefferson UniversityFollow
Ying-Hui Ko, MD, Thomas Jefferson UniversityFollow
Zhao Lin, MD, Thomas Jefferson UniversityFollow
Madalina Tuluc, MD, Department of Pathology, Thomas Jefferson UniversityFollow
David Cognetti, MD, Thomas Jefferson UniversityFollow
Ruth Birbe, MD, Thomas Jefferson UniversityFollow
Edmund A. Pribitkin, MD, Thomas Jefferson UniversityFollow
Alessandro Bombonati, Albert Einstein Medical Center
Richard Pestell, MD, Thomas Jefferson UniversityFollow
Anthony Howell, University of ManchesterFollow
Federica Sotgia, Manchester Breast Centre and Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, UK; The Jefferson Stem Cell Biology and Regenerative Medicine Center, Philadelphia, PA; Departments of Stem Cell Biology & Regenerative Medicine, and Cancer Biology, Thomas Jefferson UniversityFollow
Michael P. Lisanti, MD, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

8-15-2013

Comments

This article has been peer reviewed. It was published in: Cell Cycle.

Volume 12, Issue 16, August 2013, Pages 2580-2597.

The published version is available at DOI: 10.4161/cc.25510. Copyright © Landes Bioscience

Abstract

Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish "metabolic parasites", like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted "antibiotics" to selectively starve cancer cells. Our results provide new support for the "seed and soil" hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget.

Recommended Citation

Martinez-Outshoorn, MD, Ubaldo E.; Curry, MD, Joseph; Ko, MD, Ying-Hui; Lin, MD, Zhao; Tuluc, MD, Madalina; Cognetti, MD, David; Birbe, MD, Ruth; Pribitkin, MD, Edmund A.; Bombonati, Alessandro; Pestell, MD, Richard; Howell, Anthony; Sotgia, Federica; and Lisanti, MD, Michael P., "Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4." (2013). Kimmel Cancer Center Faculty Papers. Paper 45.
https://jdc.jefferson.edu/kimmelccfp/45

PubMed ID

23860378