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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

Autophagy-related proteins are expressed in a subset of cells within germline tumors. (A) The C. elegans gonad as a model for tumorigenesis. Anatomy of an adult hermaphrodite. One gonad arm (boxed area) is shown enlarged on the right for wild-type and gld-1 (mutant or RNAi) animal. GLD-1/quaking expression region is indicated by the green dashed line. (B) GFP::LGG-1 expression in the gonad of wild-type and gld-1 RNAi-treated animals. Left panels: Representative gonad arms reconstructed from maximum projections of gonad z-planes. Boxed areas are shown enlarged on the right. The region reconstructed is depicted in the boxed area of the scheme in panel A. (C) GFP::LGG-1 expression in the gonad of a gld-1 RNAi-treated animal from d 1 to d 9 of adulthood. Maximum projections of gonad z-planes. Boxed area in the scheme represents the region depicted in the z-projections of panels (C, D, and F) GFP::LGG-2 and BEC-1::GFP expression in the gonad of wild-type and gld-1 knockdown animals at d 3 of adulthood. Maximum projections of gonad z-planes. Scale bars: 20 μm. (E) Quantification of GFP::LGG-1 fluorescence intensity in gld-1 tumors in DMSO (control) and Baf-treated animals (n = 10 each), ***, P ≤ 0.001. (F) Representative maximum projections of GFP::mCherry::LGG-1 expressing animals. A control animal's gonad turn region (left) and a gld-1 RNAi-treated animal's germline tumor turn region (right) are shown. Boxed areas are shown enlarged on the right. Scale bar: 10 μm
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f0001: Autophagy-related proteins are expressed in a subset of cells within germline tumors. (A) The C. elegans gonad as a model for tumorigenesis. Anatomy of an adult hermaphrodite. One gonad arm (boxed area) is shown enlarged on the right for wild-type and gld-1 (mutant or RNAi) animal. GLD-1/quaking expression region is indicated by the green dashed line. (B) GFP::LGG-1 expression in the gonad of wild-type and gld-1 RNAi-treated animals. Left panels: Representative gonad arms reconstructed from maximum projections of gonad z-planes. Boxed areas are shown enlarged on the right. The region reconstructed is depicted in the boxed area of the scheme in panel A. (C) GFP::LGG-1 expression in the gonad of a gld-1 RNAi-treated animal from d 1 to d 9 of adulthood. Maximum projections of gonad z-planes. Boxed area in the scheme represents the region depicted in the z-projections of panels (C, D, and F) GFP::LGG-2 and BEC-1::GFP expression in the gonad of wild-type and gld-1 knockdown animals at d 3 of adulthood. Maximum projections of gonad z-planes. Scale bars: 20 μm. (E) Quantification of GFP::LGG-1 fluorescence intensity in gld-1 tumors in DMSO (control) and Baf-treated animals (n = 10 each), ***, P ≤ 0.001. (F) Representative maximum projections of GFP::mCherry::LGG-1 expressing animals. A control animal's gonad turn region (left) and a gld-1 RNAi-treated animal's germline tumor turn region (right) are shown. Boxed areas are shown enlarged on the right. Scale bar: 10 μm

Mentions: Germ cell-derived tumors usually result from precocious differentiation of cells in the gonads or the embryo.1 In C. elegans, induction of germline tumors can be achieved by depletion of gld-1, a member of the STAR KH-domain family of RNA binding proteins and a suppressor of translation.2 Depletion results in tumors containing fully differentiated neurons, muscle and gut cells (Fig. 1A).2 Their overproliferation leads to gonad swelling and invasion of other tissues by germline tumor cells, resulting in premature death of animals.3,4 Mutations that generally extend C. elegans life span inhibit gld-1 tumor growth and prevent tumor-dependent life-span shortening, although the mechanism is not fully understood.4 Interestingly, metabolic adjustments including upregulation of autophagy have been proposed for these long life-span mutants.5-7Figure 1.


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)

Autophagy-related proteins are expressed in a subset of cells within germline tumors. (A) The C. elegans gonad as a model for tumorigenesis. Anatomy of an adult hermaphrodite. One gonad arm (boxed area) is shown enlarged on the right for wild-type and gld-1 (mutant or RNAi) animal. GLD-1/quaking expression region is indicated by the green dashed line. (B) GFP::LGG-1 expression in the gonad of wild-type and gld-1 RNAi-treated animals. Left panels: Representative gonad arms reconstructed from maximum projections of gonad z-planes. Boxed areas are shown enlarged on the right. The region reconstructed is depicted in the boxed area of the scheme in panel A. (C) GFP::LGG-1 expression in the gonad of a gld-1 RNAi-treated animal from d 1 to d 9 of adulthood. Maximum projections of gonad z-planes. Boxed area in the scheme represents the region depicted in the z-projections of panels (C, D, and F) GFP::LGG-2 and BEC-1::GFP expression in the gonad of wild-type and gld-1 knockdown animals at d 3 of adulthood. Maximum projections of gonad z-planes. Scale bars: 20 μm. (E) Quantification of GFP::LGG-1 fluorescence intensity in gld-1 tumors in DMSO (control) and Baf-treated animals (n = 10 each), ***, P ≤ 0.001. (F) Representative maximum projections of GFP::mCherry::LGG-1 expressing animals. A control animal's gonad turn region (left) and a gld-1 RNAi-treated animal's germline tumor turn region (right) are shown. Boxed areas are shown enlarged on the right. Scale bar: 10 μm
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f0001: Autophagy-related proteins are expressed in a subset of cells within germline tumors. (A) The C. elegans gonad as a model for tumorigenesis. Anatomy of an adult hermaphrodite. One gonad arm (boxed area) is shown enlarged on the right for wild-type and gld-1 (mutant or RNAi) animal. GLD-1/quaking expression region is indicated by the green dashed line. (B) GFP::LGG-1 expression in the gonad of wild-type and gld-1 RNAi-treated animals. Left panels: Representative gonad arms reconstructed from maximum projections of gonad z-planes. Boxed areas are shown enlarged on the right. The region reconstructed is depicted in the boxed area of the scheme in panel A. (C) GFP::LGG-1 expression in the gonad of a gld-1 RNAi-treated animal from d 1 to d 9 of adulthood. Maximum projections of gonad z-planes. Boxed area in the scheme represents the region depicted in the z-projections of panels (C, D, and F) GFP::LGG-2 and BEC-1::GFP expression in the gonad of wild-type and gld-1 knockdown animals at d 3 of adulthood. Maximum projections of gonad z-planes. Scale bars: 20 μm. (E) Quantification of GFP::LGG-1 fluorescence intensity in gld-1 tumors in DMSO (control) and Baf-treated animals (n = 10 each), ***, P ≤ 0.001. (F) Representative maximum projections of GFP::mCherry::LGG-1 expressing animals. A control animal's gonad turn region (left) and a gld-1 RNAi-treated animal's germline tumor turn region (right) are shown. Boxed areas are shown enlarged on the right. Scale bar: 10 μm
Mentions: Germ cell-derived tumors usually result from precocious differentiation of cells in the gonads or the embryo.1 In C. elegans, induction of germline tumors can be achieved by depletion of gld-1, a member of the STAR KH-domain family of RNA binding proteins and a suppressor of translation.2 Depletion results in tumors containing fully differentiated neurons, muscle and gut cells (Fig. 1A).2 Their overproliferation leads to gonad swelling and invasion of other tissues by germline tumor cells, resulting in premature death of animals.3,4 Mutations that generally extend C. elegans life span inhibit gld-1 tumor growth and prevent tumor-dependent life-span shortening, although the mechanism is not fully understood.4 Interestingly, metabolic adjustments including upregulation of autophagy have been proposed for these long life-span mutants.5-7Figure 1.

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