title: Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4.
abstract: Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish "metabolic parasites", like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted "antibiotics" to selectively starve cancer cells. Our results provide new support for the "seed and soil" hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget.
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. Ubaldo.Martinez-Outschoorn@jeffersonhospital.org
authors.forename: Ubaldo E
authors.initials: UE
authors.lastname: Martinez-Outschoorn
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Curry
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Ko
authors.forename: Zhao
authors.initials: Z
authors.lastname: Lin
authors.forename: Madalina
authors.initials: M
authors.lastname: Tuluc
authors.forename: David
authors.initials: D
authors.lastname: Cognetti
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Birbe
authors.forename: Edmund
authors.initials: E
authors.lastname: Pribitkin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bombonati
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051242:Caveolin 1 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004734:Energy Metabolism / Q000502:physiology*; D004847:Epithelial Cells; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D063269:Mitochondrial Turnover / Q000187:drug effects; D008954:Models, Biological; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017154:Stromal Cells; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D051242:Caveolin 1; D018797:Cell Cycle Proteins; C115081:MCTS1 protein, human; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; C406962:SLC16A4 protein, human; D005947:Glucose; D000111:Acetylcysteine
keywords: HaCaT; MCT1; MCT4; NFkB; RAS; TOMM20; autophagy; cancer associated fibroblast; caveolin-1; field cancerization; glycolysis; inflammation; metabolic parasite; mitochondrial metabolism; oncogene; oncogenic stress; oxidative stress; response to injury; reverse Warburg effect; senescence; stromal biomarkers; tumor microenvironment; wound healing