Limits...
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

Inhibition of autophagy shortens life span of animals with tumors. (A) N2 L1 larvae were fed with the indicated RNAi(s). A representative cumulative survival curve and Kaplan Meier statistics are depicted. (B) gld-1 mutant L1 larvae were fed with the indicated dsRNAs. A cumulative survival curve and Kaplan Meier statistics are depicted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835962&req=5

f0006: Inhibition of autophagy shortens life span of animals with tumors. (A) N2 L1 larvae were fed with the indicated RNAi(s). A representative cumulative survival curve and Kaplan Meier statistics are depicted. (B) gld-1 mutant L1 larvae were fed with the indicated dsRNAs. A cumulative survival curve and Kaplan Meier statistics are depicted.

Mentions: As autophagy inhibition resulted in faster tumor growth, we asked whether it affects life span of gld-1 mutants. Overproliferation of gld-1 tumors is lethal and manifests in strongly shortened life spans when compared to wild-type animals without tumors (Fig. 6A; as reported previously refs. 3 and 4). Interfering with autophagy by lgg-3 RNAI further shortens the life span of gld-1 RNAi and mutant animals by ∼12% but did not affect wild-type life span (Fig. 6A and B).5,22 The functionality of the RNAi approach is also obvious from the changes in the ratio between lipidated/unlipidated LGG-1 (Fig. 3C).Figure 6.


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)

Inhibition of autophagy shortens life span of animals with tumors. (A) N2 L1 larvae were fed with the indicated RNAi(s). A representative cumulative survival curve and Kaplan Meier statistics are depicted. (B) gld-1 mutant L1 larvae were fed with the indicated dsRNAs. A cumulative survival curve and Kaplan Meier statistics are depicted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835962&req=5

f0006: Inhibition of autophagy shortens life span of animals with tumors. (A) N2 L1 larvae were fed with the indicated RNAi(s). A representative cumulative survival curve and Kaplan Meier statistics are depicted. (B) gld-1 mutant L1 larvae were fed with the indicated dsRNAs. A cumulative survival curve and Kaplan Meier statistics are depicted.
Mentions: As autophagy inhibition resulted in faster tumor growth, we asked whether it affects life span of gld-1 mutants. Overproliferation of gld-1 tumors is lethal and manifests in strongly shortened life spans when compared to wild-type animals without tumors (Fig. 6A; as reported previously refs. 3 and 4). Interfering with autophagy by lgg-3 RNAI further shortens the life span of gld-1 RNAi and mutant animals by ∼12% but did not affect wild-type life span (Fig. 6A and B).5,22 The functionality of the RNAi approach is also obvious from the changes in the ratio between lipidated/unlipidated LGG-1 (Fig. 3C).Figure 6.

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