Journal
CELL CYCLE
Volume 11, Issue 13, Pages 2545-2556Publisher
LANDES BIOSCIENCE
DOI: 10.4161/cc.20920
Keywords
tumor stroma; cancer-associated fibroblasts; glycolysis; autophagy; cancer metabolism; DRAM; LKB1; AMP kinase (AMPK); GOLPH3; oxidative mitochondrial metabolism (OXPHOS); DNA damage response
Categories
Funding
- Breast Cancer Alliance (BCA)
- American Cancer Society (ACS)
- Margaret Q. Landenberger Research Foundation
- NIH/NCI [R01-CA-080250, R01-CA-098779, R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072, R01-CA-107382]
- Susan G. Komen Breast Cancer Foundation
- Dr. Ralph and Marian C. Falk Medical Research Trust
- Pennsylvania Department of Health
- Centre grant in Manchester from Breakthrough Breast Cancer in the UK
- European Research Council
- NIH/NCI Cancer Center Core grant [P30-CA-56036]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available