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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 delays death caused by germline tumors in an autophagy-dependent manner and promotes neuronal differentiation. N2, atg-18 and atg-7 mutant L1 larvae were fed with gld-1 RNAi till the d 2 of adulthood and then they were either fed with bacteria expressing empty vector or fasted throughout their life span. (A) Representative cumulative survival curves and Kaplan Meier statistics are presented. (B) Top: UNC-119::mCherry L1 larvae were treated with gld-1 dsRNA till d 2 of adulthood and then treated as indicated for 1 d. Representative gonad arm reconstructed from maximum projections. Scale bar: 20 μm. Bottom left: Area occupied by UNC-119 expressing cells per gonad arm normalized by the animals kept under feeding conditions. Qualitative scoring of the gonadal area occupied by UNC-119 expressing cells was performed blindly using maximum z-projections covering whole gonad arms (d 3 of adulthood). Data represent mean ± SEM of 2 independent experiments, n = 5 (10 gonad arms), per experiment; *** P ≤ 0.001. Bottom right: Quantification of tumors with UNC-119-expressing cells. Animals were treated with the RNAis as indicated and either continued feeding or were starved for 1d before imaging and scoring. (C) Fasting-induced life span of gld-1 RNAi-treated N2, atg-18 and atg-7 mutants. For N2 and atg-18 mutant, data represent mean ± SEM of 2 independent experiments. (D) Expression profiles of transcripts in the autophagy pathway of fasted gld-1 RNAi animals compared to fed gld-1 RNAi animals. log2-fold changes are shown.
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f0007: Fasting delays death caused by germline tumors in an autophagy-dependent manner and promotes neuronal differentiation. N2, atg-18 and atg-7 mutant L1 larvae were fed with gld-1 RNAi till the d 2 of adulthood and then they were either fed with bacteria expressing empty vector or fasted throughout their life span. (A) Representative cumulative survival curves and Kaplan Meier statistics are presented. (B) Top: UNC-119::mCherry L1 larvae were treated with gld-1 dsRNA till d 2 of adulthood and then treated as indicated for 1 d. Representative gonad arm reconstructed from maximum projections. Scale bar: 20 μm. Bottom left: Area occupied by UNC-119 expressing cells per gonad arm normalized by the animals kept under feeding conditions. Qualitative scoring of the gonadal area occupied by UNC-119 expressing cells was performed blindly using maximum z-projections covering whole gonad arms (d 3 of adulthood). Data represent mean ± SEM of 2 independent experiments, n = 5 (10 gonad arms), per experiment; *** P ≤ 0.001. Bottom right: Quantification of tumors with UNC-119-expressing cells. Animals were treated with the RNAis as indicated and either continued feeding or were starved for 1d before imaging and scoring. (C) Fasting-induced life span of gld-1 RNAi-treated N2, atg-18 and atg-7 mutants. For N2 and atg-18 mutant, data represent mean ± SEM of 2 independent experiments. (D) Expression profiles of transcripts in the autophagy pathway of fasted gld-1 RNAi animals compared to fed gld-1 RNAi animals. log2-fold changes are shown.

Mentions: Since we observed that induction of autophagy, by let-363 knockdown, extends the life span of gld-1 mutants by ∼40% (Fig. 6B), we wondered whether inducing autophagy after tumors are already established would affect longevity of gld-1 animals. We triggered autophagy by uninterrupted fasting (Fig. 3C) and found that gld-1 worms fasting from d 2 of adulthood display a striking increase in life span by ∼100% (Fig. 7A). Remarkably, fasting inhibited tumor growth most likely by enhancing neuronal differentiation within the tumor (Fig. 7B), in line with a function for autophagy on tumor growth or differentiation balance.Figure 7.


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 delays death caused by germline tumors in an autophagy-dependent manner and promotes neuronal differentiation. N2, atg-18 and atg-7 mutant L1 larvae were fed with gld-1 RNAi till the d 2 of adulthood and then they were either fed with bacteria expressing empty vector or fasted throughout their life span. (A) Representative cumulative survival curves and Kaplan Meier statistics are presented. (B) Top: UNC-119::mCherry L1 larvae were treated with gld-1 dsRNA till d 2 of adulthood and then treated as indicated for 1 d. Representative gonad arm reconstructed from maximum projections. Scale bar: 20 μm. Bottom left: Area occupied by UNC-119 expressing cells per gonad arm normalized by the animals kept under feeding conditions. Qualitative scoring of the gonadal area occupied by UNC-119 expressing cells was performed blindly using maximum z-projections covering whole gonad arms (d 3 of adulthood). Data represent mean ± SEM of 2 independent experiments, n = 5 (10 gonad arms), per experiment; *** P ≤ 0.001. Bottom right: Quantification of tumors with UNC-119-expressing cells. Animals were treated with the RNAis as indicated and either continued feeding or were starved for 1d before imaging and scoring. (C) Fasting-induced life span of gld-1 RNAi-treated N2, atg-18 and atg-7 mutants. For N2 and atg-18 mutant, data represent mean ± SEM of 2 independent experiments. (D) Expression profiles of transcripts in the autophagy pathway of fasted gld-1 RNAi animals compared to fed gld-1 RNAi animals. log2-fold changes are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f0007: Fasting delays death caused by germline tumors in an autophagy-dependent manner and promotes neuronal differentiation. N2, atg-18 and atg-7 mutant L1 larvae were fed with gld-1 RNAi till the d 2 of adulthood and then they were either fed with bacteria expressing empty vector or fasted throughout their life span. (A) Representative cumulative survival curves and Kaplan Meier statistics are presented. (B) Top: UNC-119::mCherry L1 larvae were treated with gld-1 dsRNA till d 2 of adulthood and then treated as indicated for 1 d. Representative gonad arm reconstructed from maximum projections. Scale bar: 20 μm. Bottom left: Area occupied by UNC-119 expressing cells per gonad arm normalized by the animals kept under feeding conditions. Qualitative scoring of the gonadal area occupied by UNC-119 expressing cells was performed blindly using maximum z-projections covering whole gonad arms (d 3 of adulthood). Data represent mean ± SEM of 2 independent experiments, n = 5 (10 gonad arms), per experiment; *** P ≤ 0.001. Bottom right: Quantification of tumors with UNC-119-expressing cells. Animals were treated with the RNAis as indicated and either continued feeding or were starved for 1d before imaging and scoring. (C) Fasting-induced life span of gld-1 RNAi-treated N2, atg-18 and atg-7 mutants. For N2 and atg-18 mutant, data represent mean ± SEM of 2 independent experiments. (D) Expression profiles of transcripts in the autophagy pathway of fasted gld-1 RNAi animals compared to fed gld-1 RNAi animals. log2-fold changes are shown.
Mentions: Since we observed that induction of autophagy, by let-363 knockdown, extends the life span of gld-1 mutants by ∼40% (Fig. 6B), we wondered whether inducing autophagy after tumors are already established would affect longevity of gld-1 animals. We triggered autophagy by uninterrupted fasting (Fig. 3C) and found that gld-1 worms fasting from d 2 of adulthood display a striking increase in life span by ∼100% (Fig. 7A). Remarkably, fasting inhibited tumor growth most likely by enhancing neuronal differentiation within the tumor (Fig. 7B), in line with a function for autophagy on tumor growth or differentiation balance.Figure 7.

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