Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth

Carmela Guido, Diana Whitaker-Menezes, Zhao Lin, Richard G. Pestell, Anthony Howell, Teresa A. Zimmers, Mathew C. Casimiro, Saveria Aquila, Sebastiano Ando', Ubaldo E. Martinez-Outschoorn, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Recent studies have suggested that cancer cells behave as metabolic parasites, by inducing oxidative stress in adjacent normal fibroblasts. More specifically, oncogenic mutations in cancer cells lead to ROS production and the "secretion" of hydrogen peroxide species. Oxidative stress in stromal fibroblasts then induces their metabolic conversion into cancer-associated fibroblasts. Such oxidative stress drives the onset of autophagy, mitophagy, and aerobic glycolysis in fibroblasts, resulting in the local production of high-energy mitochondrial fuels (such as L-lactate, ketone bodies, and glutamine). These recycled nutrients are then transferred to cancer cells, where they are efficiently burned via oxidative mitochondrial metabolism (OXPHOS). We have termed this new energy-transfer mechanism "Two-Compartment Tumor Metabolism", to reflect that the production and consumption of nutrients (L-lactate and other catabolites) is highly compartmentalized. Thus, high-energy onco-catabolites are produced by the tumor stroma. Here, we used a genetic approach to stringently test this energy-transfer hypothesis. First, we generated hTERT-immortalized fibroblasts which were genetically re-programmed towards catabolic metabolism. Metabolic re-programming towards glycolytic metabolism was achieved by the recombinant over-expression of MFF (mitochondrial fission factor). MFF over-expression results in extensive mitochondrial fragmentation, driving mitochondrial dysfunction. Our results directly show that MFFfibroblasts undergo oxidative stress, with increased ROS production, and the onset of autophagy and mitophagy, both catabolic processes. Mechanistically, oxidative stress induces autophagy via NF-kB activation, also providing a link with inflammation. As a consequence MFF-fibroblasts showed intracellular ATP depletion and the extracellular secretion of L-lactate, a critical onco-catabolite. MFF-fibroblasts also showed signs of myofibroblast differentiation, with the expression of SMA and calponin. Importantly, MFF-fibroblasts signficantly promoted early tumor growth (up to 6.5-fold), despite a 20% overall reduction in angiogenesis. Thus, catabolic metabolism in cancer-associated fibroblasts may be a critical event during tumor intiation, allowing accelerated tumor growth, especially prior to the onset of neoangiogenesis.

Original languageEnglish (US)
Pages (from-to)798-810
Number of pages13
JournalOncotarget
Volume3
Issue number8
DOIs
StatePublished - Aug 2012

Fingerprint

Mitochondrial Dynamics
Myofibroblasts
Lactic Acid
Fibroblasts
Growth
Oxidative Stress
Neoplasms
Autophagy
Mitochondrial Degradation
Energy Transfer
Food
Ketone Bodies
NF-kappa B
Glycolysis
Glutamine
Hydrogen Peroxide
Parasites
Adenosine Triphosphate
Inflammation
Mutation

Keywords

  • Aerobic glycolysis
  • Autophagy
  • Cancer associated fibroblast
  • Cancer metabolism
  • Mitochondrial fission
  • Mitophagy
  • Myofibroblast
  • Onco-catabolite
  • Oxidative stress
  • Tumor initiation
  • Tumor stroma

ASJC Scopus subject areas

  • Oncology

Cite this

Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth. / Guido, Carmela; Whitaker-Menezes, Diana; Lin, Zhao; Pestell, Richard G.; Howell, Anthony; Zimmers, Teresa A.; Casimiro, Mathew C.; Aquila, Saveria; Ando', Sebastiano; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.

In: Oncotarget, Vol. 3, No. 8, 08.2012, p. 798-810.

Research output: Contribution to journalArticle

Guido, C, Whitaker-Menezes, D, Lin, Z, Pestell, RG, Howell, A, Zimmers, TA, Casimiro, MC, Aquila, S, Ando', S, Martinez-Outschoorn, UE, Sotgia, F & Lisanti, MP 2012, 'Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth', Oncotarget, vol. 3, no. 8, pp. 798-810. https://doi.org/10.18632/oncotarget.574
Guido, Carmela ; Whitaker-Menezes, Diana ; Lin, Zhao ; Pestell, Richard G. ; Howell, Anthony ; Zimmers, Teresa A. ; Casimiro, Mathew C. ; Aquila, Saveria ; Ando', Sebastiano ; Martinez-Outschoorn, Ubaldo E. ; Sotgia, Federica ; Lisanti, Michael P. / Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth. In: Oncotarget. 2012 ; Vol. 3, No. 8. pp. 798-810.
@article{727b8a3b6be74ecca3cad42d67574613,
title = "Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth",
abstract = "Recent studies have suggested that cancer cells behave as metabolic parasites, by inducing oxidative stress in adjacent normal fibroblasts. More specifically, oncogenic mutations in cancer cells lead to ROS production and the {"}secretion{"} of hydrogen peroxide species. Oxidative stress in stromal fibroblasts then induces their metabolic conversion into cancer-associated fibroblasts. Such oxidative stress drives the onset of autophagy, mitophagy, and aerobic glycolysis in fibroblasts, resulting in the local production of high-energy mitochondrial fuels (such as L-lactate, ketone bodies, and glutamine). These recycled nutrients are then transferred to cancer cells, where they are efficiently burned via oxidative mitochondrial metabolism (OXPHOS). We have termed this new energy-transfer mechanism {"}Two-Compartment Tumor Metabolism{"}, to reflect that the production and consumption of nutrients (L-lactate and other catabolites) is highly compartmentalized. Thus, high-energy onco-catabolites are produced by the tumor stroma. Here, we used a genetic approach to stringently test this energy-transfer hypothesis. First, we generated hTERT-immortalized fibroblasts which were genetically re-programmed towards catabolic metabolism. Metabolic re-programming towards glycolytic metabolism was achieved by the recombinant over-expression of MFF (mitochondrial fission factor). MFF over-expression results in extensive mitochondrial fragmentation, driving mitochondrial dysfunction. Our results directly show that MFFfibroblasts undergo oxidative stress, with increased ROS production, and the onset of autophagy and mitophagy, both catabolic processes. Mechanistically, oxidative stress induces autophagy via NF-kB activation, also providing a link with inflammation. As a consequence MFF-fibroblasts showed intracellular ATP depletion and the extracellular secretion of L-lactate, a critical onco-catabolite. MFF-fibroblasts also showed signs of myofibroblast differentiation, with the expression of SMA and calponin. Importantly, MFF-fibroblasts signficantly promoted early tumor growth (up to 6.5-fold), despite a 20{\%} overall reduction in angiogenesis. Thus, catabolic metabolism in cancer-associated fibroblasts may be a critical event during tumor intiation, allowing accelerated tumor growth, especially prior to the onset of neoangiogenesis.",
keywords = "Aerobic glycolysis, Autophagy, Cancer associated fibroblast, Cancer metabolism, Mitochondrial fission, Mitophagy, Myofibroblast, Onco-catabolite, Oxidative stress, Tumor initiation, Tumor stroma",
author = "Carmela Guido and Diana Whitaker-Menezes and Zhao Lin and Pestell, {Richard G.} and Anthony Howell and Zimmers, {Teresa A.} and Casimiro, {Mathew C.} and Saveria Aquila and Sebastiano Ando' and Martinez-Outschoorn, {Ubaldo E.} and Federica Sotgia and Lisanti, {Michael P.}",
year = "2012",
month = "8",
doi = "10.18632/oncotarget.574",
language = "English (US)",
volume = "3",
pages = "798--810",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "8",

}

TY - JOUR

T1 - Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth

AU - Guido, Carmela

AU - Whitaker-Menezes, Diana

AU - Lin, Zhao

AU - Pestell, Richard G.

AU - Howell, Anthony

AU - Zimmers, Teresa A.

AU - Casimiro, Mathew C.

AU - Aquila, Saveria

AU - Ando', Sebastiano

AU - Martinez-Outschoorn, Ubaldo E.

AU - Sotgia, Federica

AU - Lisanti, Michael P.

PY - 2012/8

Y1 - 2012/8

N2 - Recent studies have suggested that cancer cells behave as metabolic parasites, by inducing oxidative stress in adjacent normal fibroblasts. More specifically, oncogenic mutations in cancer cells lead to ROS production and the "secretion" of hydrogen peroxide species. Oxidative stress in stromal fibroblasts then induces their metabolic conversion into cancer-associated fibroblasts. Such oxidative stress drives the onset of autophagy, mitophagy, and aerobic glycolysis in fibroblasts, resulting in the local production of high-energy mitochondrial fuels (such as L-lactate, ketone bodies, and glutamine). These recycled nutrients are then transferred to cancer cells, where they are efficiently burned via oxidative mitochondrial metabolism (OXPHOS). We have termed this new energy-transfer mechanism "Two-Compartment Tumor Metabolism", to reflect that the production and consumption of nutrients (L-lactate and other catabolites) is highly compartmentalized. Thus, high-energy onco-catabolites are produced by the tumor stroma. Here, we used a genetic approach to stringently test this energy-transfer hypothesis. First, we generated hTERT-immortalized fibroblasts which were genetically re-programmed towards catabolic metabolism. Metabolic re-programming towards glycolytic metabolism was achieved by the recombinant over-expression of MFF (mitochondrial fission factor). MFF over-expression results in extensive mitochondrial fragmentation, driving mitochondrial dysfunction. Our results directly show that MFFfibroblasts undergo oxidative stress, with increased ROS production, and the onset of autophagy and mitophagy, both catabolic processes. Mechanistically, oxidative stress induces autophagy via NF-kB activation, also providing a link with inflammation. As a consequence MFF-fibroblasts showed intracellular ATP depletion and the extracellular secretion of L-lactate, a critical onco-catabolite. MFF-fibroblasts also showed signs of myofibroblast differentiation, with the expression of SMA and calponin. Importantly, MFF-fibroblasts signficantly promoted early tumor growth (up to 6.5-fold), despite a 20% overall reduction in angiogenesis. Thus, catabolic metabolism in cancer-associated fibroblasts may be a critical event during tumor intiation, allowing accelerated tumor growth, especially prior to the onset of neoangiogenesis.

AB - Recent studies have suggested that cancer cells behave as metabolic parasites, by inducing oxidative stress in adjacent normal fibroblasts. More specifically, oncogenic mutations in cancer cells lead to ROS production and the "secretion" of hydrogen peroxide species. Oxidative stress in stromal fibroblasts then induces their metabolic conversion into cancer-associated fibroblasts. Such oxidative stress drives the onset of autophagy, mitophagy, and aerobic glycolysis in fibroblasts, resulting in the local production of high-energy mitochondrial fuels (such as L-lactate, ketone bodies, and glutamine). These recycled nutrients are then transferred to cancer cells, where they are efficiently burned via oxidative mitochondrial metabolism (OXPHOS). We have termed this new energy-transfer mechanism "Two-Compartment Tumor Metabolism", to reflect that the production and consumption of nutrients (L-lactate and other catabolites) is highly compartmentalized. Thus, high-energy onco-catabolites are produced by the tumor stroma. Here, we used a genetic approach to stringently test this energy-transfer hypothesis. First, we generated hTERT-immortalized fibroblasts which were genetically re-programmed towards catabolic metabolism. Metabolic re-programming towards glycolytic metabolism was achieved by the recombinant over-expression of MFF (mitochondrial fission factor). MFF over-expression results in extensive mitochondrial fragmentation, driving mitochondrial dysfunction. Our results directly show that MFFfibroblasts undergo oxidative stress, with increased ROS production, and the onset of autophagy and mitophagy, both catabolic processes. Mechanistically, oxidative stress induces autophagy via NF-kB activation, also providing a link with inflammation. As a consequence MFF-fibroblasts showed intracellular ATP depletion and the extracellular secretion of L-lactate, a critical onco-catabolite. MFF-fibroblasts also showed signs of myofibroblast differentiation, with the expression of SMA and calponin. Importantly, MFF-fibroblasts signficantly promoted early tumor growth (up to 6.5-fold), despite a 20% overall reduction in angiogenesis. Thus, catabolic metabolism in cancer-associated fibroblasts may be a critical event during tumor intiation, allowing accelerated tumor growth, especially prior to the onset of neoangiogenesis.

KW - Aerobic glycolysis

KW - Autophagy

KW - Cancer associated fibroblast

KW - Cancer metabolism

KW - Mitochondrial fission

KW - Mitophagy

KW - Myofibroblast

KW - Onco-catabolite

KW - Oxidative stress

KW - Tumor initiation

KW - Tumor stroma

UR - http://www.scopus.com/inward/record.url?scp=84868625980&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868625980&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.574

DO - 10.18632/oncotarget.574

M3 - Article

C2 - 22878233

AN - SCOPUS:84868625980

VL - 3

SP - 798

EP - 810

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 8

ER -