Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells.
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.
The Jefferson Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA.
Ahmed F
AF
Salem
Diana
D
Whitaker-Menezes
Zhao
Z
Lin
Ubaldo E
UE
Martinez-Outschoorn
Herbert B
HB
Tanowitz
Mazhar Salim
MS
Al-Zoubi
Anthony
A
Howell
Richard G
RG
Pestell
Federica
F
Sotgia
Michael P
MP
Lisanti
D000091162:AMP-Activated Protein Kinase Kinases; D001343:Autophagy; D051242:Caveolin 1 / Q000378:metabolism; D002460:Cell Line; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D059016:Tumor Microenvironment
D051242:Caveolin 1; C512709:DRAM1 protein, human; C429024:GOLPH3 protein, human; D008565:Membrane Proteins; D011506:Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases