TY - JOUR
T1 - Two-compartment tumor metabolism
T2 - Autophagy in the tumor microenvironment, and oxidative mitochondrial metabolism (OXPHOS) in cancer cells
AU - Salem, Ahmed F.
AU - Whitaker-Menezes, Diana
AU - Lin, Zhao
AU - Martinez-Outschoorn, Ubaldo E.
AU - Tanowitz, Herbert B.
AU - Al-Zoubi, Mazhar Salim
AU - Howell, Anthony
AU - Pestell, Richard G.
AU - Sotgia, Federica
AU - Lisanti, Michael P.
N1 - Funding Information:
L-lactate assays. L-lactate levels were assessed according to the manufacturer’s instructions, using the EnzyChromTM L-Lactate Assay Kit (cat #ECLC-100, BioAssay Systems). For this purpose, cells were seeded in 12-well plates in complete media. The next vate AMp-kinase in cancer-associated fibroblasts, driving autophagy, Acknowledgements mitophagy and mitochondrial dysfunction. Conversely, GoLpH3 F.S. and her laboratory were supported by grants from the Breast the induction of mitochondrial biogenesis, or the enhancement of expression in cancer cells mediates autophagy resistance, likely via Cancer Alliance (BCA) and the American Cancer Society (ACS). © 2012 Landes Bioscienec. mitochondrial function. thus, compartment-specific regulation of U.E.M. was supported by a Young Investigator Award from the autophagy results in a “parasitic” form of stromal-epithelial metabolic Margaret Q. Landenberger Research Foundation. M.P.L. was coupling.HQ,hydroxy-chloroquine;RA,rapamycinanalogs.Bothchlo- supported by grants from the NIH/NCI (R01-CA-080250; roquineandrapamycinanalogscouldfunctionallydisruptmetabolic R01-CA-098779; R01-CA-120876; R01-AR-055660), and the coupling, by simultaneously turning “on” oDr “off” auotophag y inn both odtsitribute. cellular compartments (cancer cells and stromal fibroblasts). CAFs, Susan G. Komen Breast Cancer Foundation. R.G.P. was supported cancer-associatedfibroblasts. by grants from the NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was supported by the NIH/NCI Cancer Center Core grant P30-CA-56036 (to R.G.P.). Funds were also contributed by the Margaret Q. Landenberger Research Foundation (to M.P.L.). This project is funded, in part, under a grant with the Pennsylvania Department of Health (to M.P.L. and F.S.). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. This work was also supported, in part, by a Centre grant in Manchester from Breakthrough Breast Cancer in the UK (to A.H.) and an Advanced ERC Grant from the European Research Council.
PY - 2012/7/1
Y1 - 2012/7/1
N2 - 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.
AB - 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.
KW - AMP kinase (AMPK)
KW - Autophagy
KW - Cancer metabolism
KW - Cancer-associated fibroblasts
KW - DNA damage response
KW - DRAM
KW - GOLPH3
KW - Glycolysis
KW - LKB1
KW - Oxidative mitochondrial metabolism (OXPHOS)
KW - Tumor stroma
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U2 - 10.4161/cc.20920
DO - 10.4161/cc.20920
M3 - Article
C2 - 22722266
AN - SCOPUS:84863789652
SN - 1538-4101
VL - 11
SP - 2545
EP - 2559
JO - Cell Cycle
JF - Cell Cycle
IS - 13
ER -