Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells.

Authors

Ahmed F Salem, Thomas Jefferson University
Diana Whitaker-Menezes, Thomas Jefferson UniversityFollow
Zhao Lin, Thomas Jefferson UniversityFollow
Ubaldo E. Martinez-Outshoorn, Thomas Jefferson UniversityFollow
Herbert B Tanowitz, Albert Einstein College of MedicineFollow
Mazhar Salim Al-Zoubi, Thomas Jefferson UniversityFollow
Anthony Howell, University of ManchesterFollow
Richard Pestell, Thomas Jefferson UniversityFollow
Federica Sotgia, Thomas Jefferson UniversityFollow
Michael P. Lisanti, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

7-1-2012

Comments

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

Volume 11, Issue 13, July 2012, Pages 2545-2556.

The published version is available at DOI: 10.4161/cc.20920. Copyright © Landes Bioscience

Abstract

Previously, we proposed a new paradigm to explain the compartment-specific role of autophagy in tumor metabolism. In this model, autophagy and mitochondrial dysfunction in the tumor stroma promotes cellular catabolism, which results in the production of recycled nutrients. These chemical building blocks and high-energy "fuels" would then drive the anabolic growth of tumors, via autophagy resistance and oxidative mitochondrial metabolism in cancer cells. We have termed this new form of stromal-epithelial metabolic coupling: "two-compartment tumor metabolism." Here, we stringently tested this energy-transfer hypothesis, by genetically creating (1) constitutively autophagic fibroblasts, with mitochondrial dysfunction or (2) autophagy-resistant cancer cells, with increased mitochondrial function. Autophagic fibroblasts were generated by stably overexpressing key target genes that lead to AMP-kinase activation, such as DRAM and LKB1. Autophagy-resistant cancer cells were derived by overexpressing GOLPH3, which functionally promotes mitochondrial biogenesis. As predicted, DRAM and LKB1 overexpressing fibroblasts were constitutively autophagic and effectively promoted tumor growth. We validated that autophagic fibroblasts showed mitochondrial dysfunction, with increased production of mitochondrial fuels (L-lactate and ketone body accumulation). Conversely, GOLPH3 overexpressing breast cancer cells were autophagy-resistant, and showed signs of increased mitochondrial biogenesis and function, which resulted in increased tumor growth. Thus, autophagy in the tumor stroma and oxidative mitochondrial metabolism (OXPHOS) in cancer cells can both dramatically promote tumor growth, independently of tumor angiogenesis. For the first time, our current studies also link the DNA damage response in the tumor microenvironment with "Warburg-like" cancer metabolism, as DRAM is a DNA damage/repair target gene.

Recommended Citation

Salem, Ahmed F; Whitaker-Menezes, Diana; Lin, Zhao; Martinez-Outshoorn, Ubaldo E.; Tanowitz, Herbert B; Al-Zoubi, Mazhar Salim; Howell, Anthony; Pestell, Richard; Sotgia, Federica; and Lisanti, Michael P., "Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells." (2012). Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations. Paper 9.
https://jdc.jefferson.edu/stem_regenerativefp/9

PubMed ID

22722266