12 research outputs found
Social environment mediates cancer progression in Drosophila
The influence of oncogenic phenomena on the ecology and evolution of animal species is
becoming an important research topic. Similar to hostâpathogen interactions, cancer negatively
affects host fitness, which should lead to the selection of host control mechanisms,
including behavioral traits that best minimize the proliferation of malignant cells. Social
behavior is suggested to influence tumor progression. While the ecological benefits of
sociality in gregarious species are widely acknowledged, only limited data are available on the
role of the social environment on cancer progression. Here, we exposed adult Drosophila, with
colorectal-like tumors, to different social environments. We show how subtle variations in
social structure have dramatic effects on the progression of tumor growth. Finally, we reveal
that flies can discriminate between individuals at different stages of tumor development and
selectively choose their social environment accordingly. Our study demonstrates the reciprocal
links between cancer and social interactions and how sociality may impact health and
fitness in animals and its potential implications for disease ecology.This work was supported by the ANR (Blanc project EVOCAN to F.T. and project DROSONET to F.M. and C.S.), the CNRS (INEE and INSB), Fondation ARC (1555286 to J.M. and F.M.), The French league against Cancer (M27218 to J.M.), IDEEV program (to F.M.), by an International Associated Laboratory Project France/Australia, by the French-Australian Science Innovation Collaboration Program Early Career Fellowship (B.U.), by AndrĂ© Hoffmann (Fondation MAVA), Fyssen Foundation (to F.M. and E.H. D.) and the French Government (fellowship 2015â155 to M.D.)
Fatty Acid Synthase Cooperates with Glyoxalase 1 to Protect against Sugar Toxicity
International audienceFatty acid (FA) metabolism is deregulated in several human diseases including metabolic syndrome, type 2 diabetes and cancers. Therefore, FA-metabolic enzymes are potential targets for drug therapy, although the consequence of these treatments must be precisely evaluated at the organismal and cellular levels. In healthy organism, synthesis of triacylglycerols (TAGs)-composed of three FA units esterified to a glycerol backbone-is increased in response to dietary sugar. Saturation in the storage and synthesis capacity of TAGs is associated with type 2 diabetes progression. Sugar toxicity likely depends on advanced-glycation-end-products (AGEs) that form through covalent bounding between amine groups and carbonyl groups of sugar or their derivatives α-oxoaldehydes. Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that is derived from glycolysis through a non-enzymatic reaction. Glyoxalase 1 (Glo1) works to neutralize MG, reducing its deleterious effects. Here, we have used the power of Drosophila genetics to generate Fatty acid synthase (FASN) mutants, allowing us to investigate the consequence of this deficiency upon sugar-supplemented diets. We found that FASN mutants are lethal but can be rescued by an appropriate lipid diet. Rescued animals do not exhibit insulin resistance, are dramatically sensitive to dietary sugar and accumulate AGEs. We show that FASN and Glo1 cooperate at systemic and cell-autonomous levels to protect against sugar toxicity. We observed that the size of FASN mutant cells decreases as dietary sucrose increases. Genetic interactions at the cell-autonomous level, where glycolytic enzymes or Glo1 were manipulated in FASN mutant cells, revealed that this sugar-dependent size reduction is a direct consequence of MG-derived-AGE accumulation. In summary, our findings indicate that FASN is dispensable for cell growth if extracellular lipids are available. In contrast, FA-synthesis appears to be required to limit a cell-autonomous accumulation of MG-derived-AGEs, supporting the notion that MG is the most deleterious α-oxoaldehyde at the intracellular level
AGE metabolism and <i>FASN</i> deficiency.
<p>(A-B) AGE levels in <i>w</i><sup><i>-</i></sup> control (Co) and <i>FASN</i><sup><i>Î24-23</i></sup> mutant (<i>Î24-23</i>) L3 larvae raised for 24h (A) or 40h (B) (calculated from 5 samples of 10 L3 larvae); lipid and sucrose complements are indicated as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004995#pgen.1004995.g003" target="_blank">Fig. 3A-D</a>; experiment repeated twice. (C) Metabolic links between glucose catabolism, FA synthesis, AGE formation and MG detoxification. Enzymes are indicated in bold characters. (D-Dâ,E-Eâ) Developmental delay measured at puparium formation of larvae fed a LCD (D,E), a 10%-SSD (Dâ,Eâ) or a 20%-SSD (Dâ,Eâ). (D-Dâ) The <i>Cg-gal4</i> driver was used to direct RNAi to <i>glo1</i>, <i>FASN</i><sup><i>CG3523</i></sup> or both together within the FB. In (D-Dâ), each curve represents at least 300 animas; experiment repeated twice. (E-Eâ) The <i>Cg-gal4</i> driver was used to direct <i>FASN</i><sup><i>CG3523</i></sup><i>-RNAi</i>, <i>UAS-glo1</i>, or both together. Controls (Co) are progeny resulting from the cross between <i>Cg-gal4</i> females and <i>w</i><sup><i>-</i></sup> balanced males. In (E-Eâ), each curve represents at least 700 animals.</p
Cell-autonomous defect in <i>FASN</i> mutant FB cells.
<p>(A-L) Phalloidin staining of FB from feeding L3 larvae containing MARCM clones labeled with GFP. At the top right corner of each image, the genotype of the clonal cells and the percentage of sucrose supplementation are shown in green and yellow, respectively. <i>FASN</i><sup><i>Î24-23</i></sup> (<i>Î24-23</i>), <i>PFK1-RNAi</i> (<i>PFK1-Ri</i>), <i>PK-RNAi</i> (<i>PK-Ri</i>), <i>glo1-RNAi</i> (<i>glo1-Ri</i>) and <i>UAS-glo1</i> (+<i>glo1</i>). Scale bars: 20ÎŒm. (M-P) Size ratio between at least ten clonal cells and the neighbouring control cells, as shown in A, B, C, D (M), E, F, G, H (N), I, J, K (O) and L (P). For each condition, at least 10 larvae were dissected; whilst searching for <i>FASN</i><sup><i>Î24-23</i></sup> clones expressing <i>glo1-RNAi</i> in larvae fed a 20%-SSD at least 40 animals were dissected.</p
Sugar sensitivity of <i>FASN</i> null mutants.
<p>(A) Survival until metamorphosis or early larval lethality (<b>â </b>) of <i>w</i><sup><i>-</i></sup> control (Co) and <i>FASN</i><sup><i>Î24-23</i></sup> mutant (<i>Î24-23</i>) animals fed either a LCD (Lipids -) or a beySD (Lipids +) with (10%) or without (0%) additional sugar. For each condition, the mean of survival rate was calculated by assessing the number of newly hatched larvae reaching metamorphosis (groups of 100 L1 larvae placed in 5 separate tubes). (B-D) Metabolic measurements from <i>w</i><sup><i>-</i></sup> control (Co) or <i>FASN</i><sup><i>Î24-23</i></sup> mutant (<i>Î24-23</i>) larvae that were fed a beySD until L2/L3 transition and then transferred onto fresh media (0%) or media containing additional sucrose (10%) for 24h. (B) Blue dye accumulation in 24h old L3 larvae after feeding on a tinted media for 1h (means calculated from 3 samples of 10 feeding L3 larvae); experiments repeated 3 times. (C-D) Circulating glucose (C) and trehalose (D) levels from bled larvae (means calculated from 4 samples of 20 to 30 bled L3 larvae); experiment repeated 3 times. (E-L) Membrane localization of tGPH in FB explants incubated with (F,H,J,L) or without (E,G,I,K) insulin (0,5 ÎŒM) (for quantification of tGPH intensity see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004995#pgen.1004995.s004" target="_blank">S4B Fig</a>.). FB explants were dissected from <i>w</i><sup><i>-</i></sup> control (E,F,I,J) or <i>FASN</i><sup><i>Î24-23</i></sup> (G,H,K,L) L3 larvae that were fed a beySD (E-H) or the same media supplemented with 10% sucrose (I-L) for 24h. For each genotype, at least 10 larvae were dissected; experiment repeated twice. Scale bars: 20ÎŒm.</p
Characterization of <i>FASN</i> mutants.
<p>(A) Locus of the <i>FASN</i><sup><i>CG3523</i></sup>, <i>FASN</i><sup><i>CG3524</i></sup> genes. The blue triangles show the two P-element insertions used to generate the <i>FASN</i><sup><i>Î24</i></sup> deficiency. The dotted lines indicate the genomic sequences removed in <i>FASN</i><sup><i>Î24</i></sup> and <i>FASN</i><sup><i>Î24-23</i></sup> mutants. The ketoacyl synthase (KS), malonyl acyl transferase (MAT), dehydratase (DH), enoyl reductase (ER) ketoreductase (KR), acyl carrier protein (ACP) and thioesterase (TE) domains of FASN<sup>CG3523</sup> are indicated. (B) RT-Q-PCR (means calculated from 3 samples of 10 feeding L3 larvae) to <i>FASN</i><sup><i>CG3523</i></sup> (left) and <i>FASN</i><sup><i>CG3524</i></sup> (right) in <i>w</i><sup><i>-</i></sup> control (Co), <i>FASN</i><sup><i>Î24</i></sup> (<i>Î24</i>) and <i>FASN</i><sup><i>Î24-23</i></sup> (<i>Î24-23</i>) mutants rescued by dietary lipids or the <i>UAS-FASN</i><sup><i>CG3523</i></sup> transgene (<i>Î24+</i> and <i>Î24-23+</i>). (C-F) Concentration of TAGs (C), glycogen (D), trehalose (E) and glucose (F) in <i>w</i><sup><i>-</i></sup> control (Co) or <i>FASN</i><sup><i>Î24-23</i></sup> (<i>Î24-23</i>) mutant prepupae raised on the rescuing lipid media. (G-H) FA profiles of the sterol esters (G) and TAGs (H) classes from either <i>w</i><sup><i>-</i></sup> control (Co) or <i>FASN</i><sup><i>Î24-23</i></sup> (<i>Î24-23</i>) mutant prepupae raised on a beySD. Fatty acid species [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004995#pgen.1004995.ref071" target="_blank">71</a>] are indicated at the bottom of each panel. TAGs values are means calculated from 5 samples of 150 mg 0â5h prepupae; glucose, trehalose and glycogen values are means calculated from 4 samples of 500 mg 0â5h prepupae. Fatty acid profiles represent means calculated from 3 samples of 100 mg 0â5h prepupae.</p
<i>GlyS</i>, <i>ACC and FASN</i><sup><i>CG3523</i></sup> expression is induced by and protects from dietary sugar.
<p>(A) RT-Q-PCR (means calculated from 3 samples of 10 feeding L3 larvae) to <i>GlyS</i>, <i>ACC</i>, <i>FASN</i><sup><i>CG3523</i></sup>, <i>FASN</i><sup><i>CG3524</i></sup> and <i>FASN</i><sup><i>CG17374</i></sup> in response to increasing concentration of dietary sucrose (0%, 5%, 10%, 20%). (B-D) Developmental delay was measured at puparium formation of larvae fed a LCD (B), a 10%-SSD (C) or a 20%-SSD (D). The <i>Cg-gal4</i> driver was used to direct RNAi to <i>GlyS</i>, <i>ACC</i> or <i>FASN</i><sup><i>CG3523</i></sup> within the FB. The <i>Cg-gal4</i> was combined with a <i>UAS-Dcr2</i> transgene to strengthen the RNAi effect. Controls (Co) were progeny resulting from the cross between <i>Cg-gal4</i> females and <i>w</i><sup><i>-</i></sup> balanced males. In (B-D), each curve represents at least 300 animals; experiment repeated twice.</p
Glucose metabolic fate in the larval FB.
<p>(A) Under normal conditions, glucose that enters into FB cells is mainly used through glycolysis and FA synthesis for TAG storage. Glucose is also stored as glycogen. Small amounts of MG are formed; thus Glo1 activity is not critical. (B) In <i>FASN</i> mutant FB cells, FA synthesis is abolished and glycogen synthesis is increased. Excess of sugar provokes a dramatic increase in MG levels and elicits Glo1 activity.</p
AGE metabolism and <i>FASN</i> deficiency.
<p>(A-B) AGE levels in <i>w</i><sup><i>-</i></sup> control (Co) and <i>FASN</i><sup><i>Î24-23</i></sup> mutant (<i>Î24-23</i>) L3 larvae raised for 24h (A) or 40h (B) (calculated from 5 samples of 10 L3 larvae); lipid and sucrose complements are indicated as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004995#pgen.1004995.g003" target="_blank">Fig. 3A-D</a>; experiment repeated twice. (C) Metabolic links between glucose catabolism, FA synthesis, AGE formation and MG detoxification. Enzymes are indicated in bold characters. (D-Dâ,E-Eâ) Developmental delay measured at puparium formation of larvae fed a LCD (D,E), a 10%-SSD (Dâ,Eâ) or a 20%-SSD (Dâ,Eâ). (D-Dâ) The <i>Cg-gal4</i> driver was used to direct RNAi to <i>glo1</i>, <i>FASN</i><sup><i>CG3523</i></sup> or both together within the FB. In (D-Dâ), each curve represents at least 300 animas; experiment repeated twice. (E-Eâ) The <i>Cg-gal4</i> driver was used to direct <i>FASN</i><sup><i>CG3523</i></sup><i>-RNAi</i>, <i>UAS-glo1</i>, or both together. Controls (Co) are progeny resulting from the cross between <i>Cg-gal4</i> females and <i>w</i><sup><i>-</i></sup> balanced males. In (E-Eâ), each curve represents at least 700 animals.</p