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

Ahmed F. Salem, Diana Whitaker-Menezes, Zhao Lin, Ubaldo E. Martinez-Outschoorn, Herbert B. Tanowitz, Mazhar Salim Al-Zoubi, Anthony Howell, Richard G. Pestell, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

74 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2545-2559
Number of pages15
JournalCell Cycle
Volume11
Issue number13
DOIs
Publication statusPublished - Jul 1 2012

    Fingerprint

Keywords

  • AMP kinase (AMPK)
  • Autophagy
  • Cancer metabolism
  • Cancer-associated fibroblasts
  • DNA damage response
  • DRAM
  • GOLPH3
  • Glycolysis
  • LKB1
  • Oxidative mitochondrial metabolism (OXPHOS)
  • Tumor stroma

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Salem, A. F., Whitaker-Menezes, D., Lin, Z., Martinez-Outschoorn, U. E., Tanowitz, H. B., Al-Zoubi, M. S., ... Lisanti, M. P. (2012). Two-compartment tumor metabolism: Autophagy in the tumor microenvironment, and oxidative mitochondrial metabolism (OXPHOS) in cancer cells. Cell Cycle, 11(13), 2545-2559. https://doi.org/10.4161/cc.20920