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Autophagy and modular restructuring of metabolism control germline tumor differentiation and proliferation in C. elegans.

Gomes LC, Odedra D, Dikic I, Pohl C - Autophagy (2016)

Bottom Line: To understand how autophagy plays this dual role in cancer, in vivo models are required.Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism.Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.

View Article: PubMed Central - PubMed

Affiliation: a Buchmann Institute for Molecular Life Sciences, Goethe University , Frankfurt (Main) , Germany.

ABSTRACT
Autophagy can act either as a tumor suppressor or as a survival mechanism for established tumors. To understand how autophagy plays this dual role in cancer, in vivo models are required. By using a highly heterogeneous C. elegans germline tumor, we show that autophagy-related proteins are expressed in a specific subset of tumor cells, neurons. Inhibition of autophagy impairs neuronal differentiation and increases tumor cell number, resulting in a shorter life span of animals with tumors, while induction of autophagy extends their life span by impairing tumor proliferation. Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism. Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.

No MeSH data available.


Related in: MedlinePlus

Fasting induces modular changes in the metabolic gene regulatory network. (A) KEGG pathway enrichment analysis of gld-1 RNAi animals that were fasted. Only upregulated pathways in fasted compared to fed gld-1 RNAi animals with P values lower than 0.01 are shown. (B) Changes in transcript levels in selected carbohydrate and branched-chain amino acid catabolism pathways. log2-fold changes between fasting and feeding are shown. (circled numbers: 1 = glycolysis; 2 = gluconeogenesis; 3 = glycogen metabolism; 4 = propionate metabolism). (C) Changes in transcript levels in fatty acid and mitochondrial metabolic pathways. log2-fold changes between fasting and feeding are shown. log2-scale as in panel (B). (circled numbers: 5 = fatty acid synthesis; 6 = ß-oxidation; 7 = tricarboxylic acid (TCA) cycle, mitochondrial catabolism) (D) Changes in transcript levels in module 142 from ref. 42. log2-fold changes between fasting and feeding are shown. (E) Core metabolic processes in C. elegans and the pathways identified to be regulated after fasting (circled numbers, see above). PEP = phosphoenol-pyruvate, OXPHOS = oxidative phosphorylation. (F) Left: Changes in transcript levels in modules II and III from ref. 45. log2-fold changes between fasting and feeding are shown. Right: Connection between the metabolic regulators in module III. Colors represent log2-fold changes. (G) NHR-178 and NHR-49 expression in germline tumors and regulation by fasting. Left: Representative z-projections of central germline tumor regions of the indicated transgenic animals. Scale bar: 10 μm. Right: Quantification of tumor cells expressing NHR-49 (blue) or NHR-178 (red) at d 3 of adulthood with or without starvation for 1 d; n = 3 animals each; *P ≤ 0.05; **P ≤ 0.01.
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f0008: Fasting induces modular changes in the metabolic gene regulatory network. (A) KEGG pathway enrichment analysis of gld-1 RNAi animals that were fasted. Only upregulated pathways in fasted compared to fed gld-1 RNAi animals with P values lower than 0.01 are shown. (B) Changes in transcript levels in selected carbohydrate and branched-chain amino acid catabolism pathways. log2-fold changes between fasting and feeding are shown. (circled numbers: 1 = glycolysis; 2 = gluconeogenesis; 3 = glycogen metabolism; 4 = propionate metabolism). (C) Changes in transcript levels in fatty acid and mitochondrial metabolic pathways. log2-fold changes between fasting and feeding are shown. log2-scale as in panel (B). (circled numbers: 5 = fatty acid synthesis; 6 = ß-oxidation; 7 = tricarboxylic acid (TCA) cycle, mitochondrial catabolism) (D) Changes in transcript levels in module 142 from ref. 42. log2-fold changes between fasting and feeding are shown. (E) Core metabolic processes in C. elegans and the pathways identified to be regulated after fasting (circled numbers, see above). PEP = phosphoenol-pyruvate, OXPHOS = oxidative phosphorylation. (F) Left: Changes in transcript levels in modules II and III from ref. 45. log2-fold changes between fasting and feeding are shown. Right: Connection between the metabolic regulators in module III. Colors represent log2-fold changes. (G) NHR-178 and NHR-49 expression in germline tumors and regulation by fasting. Left: Representative z-projections of central germline tumor regions of the indicated transgenic animals. Scale bar: 10 μm. Right: Quantification of tumor cells expressing NHR-49 (blue) or NHR-178 (red) at d 3 of adulthood with or without starvation for 1 d; n = 3 animals each; *P ≤ 0.05; **P ≤ 0.01.

Mentions: Functional clustering showed a modular reshuffle of metabolism in fasted, gld-1-depleted animals (Fig. 8A). A consistent upregulation of genes involved in fatty acid β−oxidation, citric acid cycle, amino acid and propionate catabolism (Fig. 8B and C; Table S5) was detected in fasted gld-1 RNAi animals. Conversely, fatty acid synthesis genes are downregulated in fasted animals (Fig. 8C). Regarding carbohydrate metabolism, upregulation of genes involved in glycolysis, gluconeogenesis and glycogenesis was detected (Fig. 8B). In line with a metabolic reorganization in fasted gld-1 animals, module 142 ‘Generation of precursor metabolites and energy, positive regulation of growth, ion transport’ described by Vermeirssen and colleagues42 is coregulated in fasted animals (Fig. 8D; all components except cst-1 and dox-1, which are also found inversely regulated in other experiments42). This module was identified using transcription profiles from various experiments by applying a reverse-engineering algorithm to extract ensembles of coexpressed genes. Module 142 is related to mitochondrial metabolism and contains transcripts of the mitochondrial phosphate carrier F01G4.6, the complex IV subunit F26E4.6, the ATP synthase subunits F58F12.1 and H28O16.1, the outer membrane voltage-gated anion channel vdac-1, the fructose bisphosphate aldolase aldo-2, and the peroxidase prdx-2. Taken together, the coregulation of several metabolic pathways and of module 142 during fasting leads to an upregulation of the major catabolic pathways and a downregulation of fatty acid synthesis, suggesting that mitochondrial respiration will increase under these conditions (Fig. 8E).Figure 8.


Autophagy and modular restructuring of metabolism control germline tumor differentiation and proliferation in C. elegans.

Gomes LC, Odedra D, Dikic I, Pohl C - Autophagy (2016)

Fasting induces modular changes in the metabolic gene regulatory network. (A) KEGG pathway enrichment analysis of gld-1 RNAi animals that were fasted. Only upregulated pathways in fasted compared to fed gld-1 RNAi animals with P values lower than 0.01 are shown. (B) Changes in transcript levels in selected carbohydrate and branched-chain amino acid catabolism pathways. log2-fold changes between fasting and feeding are shown. (circled numbers: 1 = glycolysis; 2 = gluconeogenesis; 3 = glycogen metabolism; 4 = propionate metabolism). (C) Changes in transcript levels in fatty acid and mitochondrial metabolic pathways. log2-fold changes between fasting and feeding are shown. log2-scale as in panel (B). (circled numbers: 5 = fatty acid synthesis; 6 = ß-oxidation; 7 = tricarboxylic acid (TCA) cycle, mitochondrial catabolism) (D) Changes in transcript levels in module 142 from ref. 42. log2-fold changes between fasting and feeding are shown. (E) Core metabolic processes in C. elegans and the pathways identified to be regulated after fasting (circled numbers, see above). PEP = phosphoenol-pyruvate, OXPHOS = oxidative phosphorylation. (F) Left: Changes in transcript levels in modules II and III from ref. 45. log2-fold changes between fasting and feeding are shown. Right: Connection between the metabolic regulators in module III. Colors represent log2-fold changes. (G) NHR-178 and NHR-49 expression in germline tumors and regulation by fasting. Left: Representative z-projections of central germline tumor regions of the indicated transgenic animals. Scale bar: 10 μm. Right: Quantification of tumor cells expressing NHR-49 (blue) or NHR-178 (red) at d 3 of adulthood with or without starvation for 1 d; n = 3 animals each; *P ≤ 0.05; **P ≤ 0.01.
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Related In: Results  -  Collection

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f0008: Fasting induces modular changes in the metabolic gene regulatory network. (A) KEGG pathway enrichment analysis of gld-1 RNAi animals that were fasted. Only upregulated pathways in fasted compared to fed gld-1 RNAi animals with P values lower than 0.01 are shown. (B) Changes in transcript levels in selected carbohydrate and branched-chain amino acid catabolism pathways. log2-fold changes between fasting and feeding are shown. (circled numbers: 1 = glycolysis; 2 = gluconeogenesis; 3 = glycogen metabolism; 4 = propionate metabolism). (C) Changes in transcript levels in fatty acid and mitochondrial metabolic pathways. log2-fold changes between fasting and feeding are shown. log2-scale as in panel (B). (circled numbers: 5 = fatty acid synthesis; 6 = ß-oxidation; 7 = tricarboxylic acid (TCA) cycle, mitochondrial catabolism) (D) Changes in transcript levels in module 142 from ref. 42. log2-fold changes between fasting and feeding are shown. (E) Core metabolic processes in C. elegans and the pathways identified to be regulated after fasting (circled numbers, see above). PEP = phosphoenol-pyruvate, OXPHOS = oxidative phosphorylation. (F) Left: Changes in transcript levels in modules II and III from ref. 45. log2-fold changes between fasting and feeding are shown. Right: Connection between the metabolic regulators in module III. Colors represent log2-fold changes. (G) NHR-178 and NHR-49 expression in germline tumors and regulation by fasting. Left: Representative z-projections of central germline tumor regions of the indicated transgenic animals. Scale bar: 10 μm. Right: Quantification of tumor cells expressing NHR-49 (blue) or NHR-178 (red) at d 3 of adulthood with or without starvation for 1 d; n = 3 animals each; *P ≤ 0.05; **P ≤ 0.01.
Mentions: Functional clustering showed a modular reshuffle of metabolism in fasted, gld-1-depleted animals (Fig. 8A). A consistent upregulation of genes involved in fatty acid β−oxidation, citric acid cycle, amino acid and propionate catabolism (Fig. 8B and C; Table S5) was detected in fasted gld-1 RNAi animals. Conversely, fatty acid synthesis genes are downregulated in fasted animals (Fig. 8C). Regarding carbohydrate metabolism, upregulation of genes involved in glycolysis, gluconeogenesis and glycogenesis was detected (Fig. 8B). In line with a metabolic reorganization in fasted gld-1 animals, module 142 ‘Generation of precursor metabolites and energy, positive regulation of growth, ion transport’ described by Vermeirssen and colleagues42 is coregulated in fasted animals (Fig. 8D; all components except cst-1 and dox-1, which are also found inversely regulated in other experiments42). This module was identified using transcription profiles from various experiments by applying a reverse-engineering algorithm to extract ensembles of coexpressed genes. Module 142 is related to mitochondrial metabolism and contains transcripts of the mitochondrial phosphate carrier F01G4.6, the complex IV subunit F26E4.6, the ATP synthase subunits F58F12.1 and H28O16.1, the outer membrane voltage-gated anion channel vdac-1, the fructose bisphosphate aldolase aldo-2, and the peroxidase prdx-2. Taken together, the coregulation of several metabolic pathways and of module 142 during fasting leads to an upregulation of the major catabolic pathways and a downregulation of fatty acid synthesis, suggesting that mitochondrial respiration will increase under these conditions (Fig. 8E).Figure 8.

Bottom Line: To understand how autophagy plays this dual role in cancer, in vivo models are required.Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism.Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.

View Article: PubMed Central - PubMed

Affiliation: a Buchmann Institute for Molecular Life Sciences, Goethe University , Frankfurt (Main) , Germany.

ABSTRACT
Autophagy can act either as a tumor suppressor or as a survival mechanism for established tumors. To understand how autophagy plays this dual role in cancer, in vivo models are required. By using a highly heterogeneous C. elegans germline tumor, we show that autophagy-related proteins are expressed in a specific subset of tumor cells, neurons. Inhibition of autophagy impairs neuronal differentiation and increases tumor cell number, resulting in a shorter life span of animals with tumors, while induction of autophagy extends their life span by impairing tumor proliferation. Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism. Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.

No MeSH data available.


Related in: MedlinePlus