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• W2909969237 abstract "•yki3SA tumors activate systemic MEK signaling to cause tumor growth and host wasting•Pharmaceutical MEK inhibition in host tissues alone alleviates wasting•yki3SA tumors produce vn to autonomously promote MEK signaling and tumor growth•yki3SA tumors produce Pvf1 to non-autonomously trigger host MEK signaling and wasting Interactions between tumors and host tissues play essential roles in tumor-induced systemic wasting and cancer cachexia, including muscle wasting and lipid loss. However, the pathogenic molecular mechanisms of wasting are still poorly understood. Using a fly model of tumor-induced organ wasting, we observed aberrant MEK activation in both tumors and host tissues of flies bearing gut-yki3SA tumors. We found that host MEK activation results in muscle wasting and lipid loss, while tumor MEK activation is required for tumor growth. Strikingly, host MEK suppression alone is sufficient to abolish the wasting phenotypes without affecting tumor growth. We further uncovered that yki3SA tumors produce the vein (vn) ligand to trigger autonomous Egfr/MEK-induced tumor growth and produce the PDGF- and VEGF-related factor 1 (Pvf1) ligand to non-autonomously activate host Pvr/MEK signaling and wasting. Altogether, our results demonstrate the essential roles and molecular mechanisms of differential MEK activation in tumor-induced host wasting. Interactions between tumors and host tissues play essential roles in tumor-induced systemic wasting and cancer cachexia, including muscle wasting and lipid loss. However, the pathogenic molecular mechanisms of wasting are still poorly understood. Using a fly model of tumor-induced organ wasting, we observed aberrant MEK activation in both tumors and host tissues of flies bearing gut-yki3SA tumors. We found that host MEK activation results in muscle wasting and lipid loss, while tumor MEK activation is required for tumor growth. Strikingly, host MEK suppression alone is sufficient to abolish the wasting phenotypes without affecting tumor growth. We further uncovered that yki3SA tumors produce the vein (vn) ligand to trigger autonomous Egfr/MEK-induced tumor growth and produce the PDGF- and VEGF-related factor 1 (Pvf1) ligand to non-autonomously activate host Pvr/MEK signaling and wasting. Altogether, our results demonstrate the essential roles and molecular mechanisms of differential MEK activation in tumor-induced host wasting. Many patients with advanced cancer exhibit a systemic wasting syndrome, referred to as “cancer cachexia,” with major features of progressive loss of muscle and adipose tissues. Cachexia is associated with poor chemotherapy response, reduced life quality, and increased mortality (Fearon et al., 2013Fearon K. Arends J. Baracos V. Understanding the mechanisms and treatment options in cancer cachexia.Nat. Rev. Clin. Oncol. 2013; 10: 90-99Crossref PubMed Scopus (587) Google Scholar). Unlike malnutrition conditions, cachexia can rarely be reversed by nutritional supplementation and is frequently accompanied with hyperglycemia (Chevalier and Farsijani, 2014Chevalier S. Farsijani S. Cancer cachexia and diabetes: similarities in metabolic alterations and possible treatment.Appl. Physiol. Nutr. Metab. 2014; 39: 643-653Crossref PubMed Scopus (21) Google Scholar). A number of findings in cultured cells have indicated that in addition to systemic inflammatory responses, tumors produce secreted factors (e.g., interleukins and activins) that directly target myotubes and adipocytes to cause myotube wasting and lipid loss, respectively (Miyamoto et al., 2016Miyamoto Y. Hanna D.L. Zhang W. Baba H. Lenz H.J. Molecular pathways: cachexia signaling-a targeted approach to cancer treatment.Clin. Cancer Res. 2016; 22: 3999-4004Crossref PubMed Scopus (67) Google Scholar). Antibody neutralization of tumor-derived cachectic ligands (PTHrP) also significantly improves host wasting (Kir et al., 2014Kir S. White J.P. Kleiner S. Kazak L. Cohen P. Baracos V.E. Spiegelman B.M. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia.Nature. 2014; 513: 100-104Crossref PubMed Scopus (402) Google Scholar). Despite these advances, genetic animal models to comprehensively assess tumor-secreted ligands, the signaling pathways they regulate, and their effects in various tissues are far less established. The adult Drosophila midgut has emerged as a model system to study tumorigenesis. Many mutations involved in human cancer have been found to result in overproliferation of fly intestinal stem cells (ISCs) and tumor formation (Patel and Edgar, 2014Patel P.H. Edgar B.A. Tissue design: how Drosophila tumors remodel their neighborhood.Semin. Cell Dev. Biol. 2014; 28: 86-95Crossref PubMed Scopus (18) Google Scholar). The fly midgut has also been established as a conserved genetic model to study tumor-induced host wasting. We found that induction of an active oncogene yorkie (yki3SA), the homolog of human Yap1, that causes gut tumor formation is associated with organ wasting phenotypes, including muscle dysfunction, lipid loss, and hyperglycemia. Mechanisms included that yki3SA-gut tumors produce the IGF-antagonizing peptide ImpL2 that suppresses systemic insulin signaling and anabolism and contributes to host wasting (Kwon et al., 2015Kwon Y. Song W. Droujinine I.A. Hu Y. Asara J.M. Perrimon N. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2.Dev. Cell. 2015; 33: 36-46Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). In addition, ImpL2 regulation of host wasting has also been observed in transplanted tumors that are generated from fly imaginal discs (Figueroa-Clarevega and Bilder, 2015Figueroa-Clarevega A. Bilder D. Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting.Dev. Cell. 2015; 33: 47-55Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Together, these findings emphasize that communication between tumor and host organs is a general phenomenon, and that Drosophila can be used to dissect the molecular mechanisms involved in tumor-host interaction. The MEK/ERK cascade is a highly conserved mitogen-activated protein kinase (MAPK) pathway involved in various biological regulations in both fly and mammals (Friedman and Perrimon, 2006Friedman A. Perrimon N. High-throughput approaches to dissecting MAPK signaling pathways.Methods. 2006; 40: 262-271Crossref PubMed Scopus (27) Google Scholar). MEK signaling, in addition to controlling cell proliferation, promotes muscle atrophy via modulation of ubiquitin-dependent protein degradation and enhances lipid mobilization via modulating GPCR/cAMP cascade (Hong et al., 2018Hong S. Song W. Zushin P.H. Liu B. Jedrychowski M.P. Mina A.I. Deng Z. Cabarkapa D. Hall J.A. Palmer C.J. et al.Phosphorylation of beta-3 adrenergic receptor at serine 247 by ERK MAP kinase drives lipolysis in obese adipocytes.Mol. Metab. 2018; 12: 25-38Crossref PubMed Scopus (43) Google Scholar, Zheng et al., 2010Zheng B. Ohkawa S. Li H. Roberts-Wilson T.K. Price S.R. FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy.FASEB J. 2010; 24: 2660-2669Crossref PubMed Scopus (97) Google Scholar). These results indicate that MEK signaling is associated with loss of muscle and adipose tissues, the main features of cancer cachexia, and suggest that MEK activation may be involved in tumor-induced host wasting. However, administration of MEK inhibitors in tumor-bearing mice and patients are associated with inconsistent results (Au et al., 2016Au E.D. Desai A.P. Koniaris L.G. Zimmers T.A. The MEK-inhibitor selumetinib attenuates tumor growth and reduces IL-6 expression but does not protect against muscle wasting in Lewis lung cancer cachexia.Front. Physiol. 2016; 7: 682PubMed Google Scholar, Prado et al., 2012Prado C.M.M. Bekaii-Saab T. Doyle L.A. Shrestha S. Ghosh S. Baracos V.E. Sawyer M.B. Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma.Br. J. Cancer. 2012; 106: 1583-1586Crossref PubMed Scopus (89) Google Scholar, Quan-Jun et al., 2017Quan-Jun Y. Yan H. Yong-Long H. Li-Li W. Jie L. Jin-Lu H. Jin L. Peng-Guo C. Run G. Cheng G. Selumetinib attenuates skeletal muscle wasting in murine cachexia model through ERK inhibition and AKT activation.Mol. Cancer Ther. 2017; 16: 334-343Crossref PubMed Scopus (40) Google Scholar). In this study, we revealed aberrant MEK activation in both tumors and host tissues (muscle and fat body) of flies bearing yki3SA-gut tumors. In the context of gut-tumor growth, pharmaceutical inhibition of MEK signaling in the host tissues alone is sufficient to alleviate host wasting, including muscle wasting, lipid loss, hyperglycemia, and elevated mortality, in tumor-bearing flies. Integrating RNA sequencing (RNA-seq) and RNA interference (RNAi) screening, we demonstrate that yki3SA-gut tumors produce the Pvf1 ligand to activate MEK signaling and enhance catabolism in host tissues. yki3SA-gut tumors also produce the vn ligand to autonomously promote MEK signaling and self-growth. To analyze the role of MEK/ERK signaling in tumor-host interaction, we first examined whether MEK signaling is activated in host tissues during tumor-induced wasting. We expressed an activated form of yorkie (yki3SA, ykiS111A-S168A-S250A triple mutant) in adult ISCs using the temperature-sensitive GAL4 driver to trigger the development of GFP-labeled gut tumors (esg-GAL4, tub-GAL80TS, UAS-GFP/+; UAS-yki3SA/+, referred to as yki3SA tumors) and host wasting (Figures 1A and S1A–S1G). Interestingly, the canonical readout of MEK signaling, pdERK (encoded by rl), in the muscle and fat body remained unchanged at day 2 of tumor induction (referred to as the “proliferation” state) but was significantly increased at day 4 (yki3SA tumors expand to the whole midgut [referred to as the “tumorigenesis” state]), day 6 (tumor-bearing flies exhibit swollen abdomen and moderate TAG decrease and muscle dysfunction [referred to as the “ascites” state]), and day 8 (tumor-bearing flies exhibit translucent abdomen, severe TAG decrease and carbohydrate increase, and muscle dysfunction [referred as the “wasting or bloating” state]) (Figures 1A–1C and S1A–S1G). These observations indicate that MEK signaling is activated in host tissues during yki3SA-tumor-induced wasting. Further, we manipulated MEK signaling specifically in wild-type muscle or fat body. Consistent with yki3SA-tumor-bearing flies (Figures S1E–S1G), specific activation of MEK signaling via expression of an activated form of Raf (Raf F179) or simply wild-type dERK in the wild-type muscle resulted in muscle-wasting phenotypes, including enhanced muscular protein degradation, impairment of myofiber integrity (gaps between myofibers and mitochondria as indicated), and climbing defects (Figures 1D–1G). MEK suppression via dERK knockdown in wild-type muscles decreased protein degradation and improved fly climbing ability (Figures 1D–1G). MEK signaling manipulation in wild-type fat bodies significantly affected lipolysis rate and lipid storage (Figures 1H–1K, and S1H), phenocopying lipid dysregulation in yki3SA-tumor-bearing flies (Figures S1A and S1I). Thus, our results demonstrate that MEK activation in host tissues results in muscle wasting and lipid loss. We next tested whether host MEK inhibition is sufficient to alleviate tumor-induced wasting. As systemic disruption of MEK signaling causes developmental lethality, we fed flies trametinib (Tram), an efficient MEK inhibitor (Slack et al., 2015Slack C. Alic N. Foley A. Cabecinha M. Hoddinott M.P. Partridge L. The Ras-erk-ETS-signaling pathway is a drug target for longevity.Cell. 2015; 162: 72-83Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). We initially fed flies normal food containing 10 μM or 100 μM Tram at tumor initiation (day 0). Both doses resulted in the strong MEK suppression in host tissues and diminished the bloating or wasting phenotypes of yki3SA-tumor-bearing flies at day 8 (Figures 2A and 2B ). However, we observed a strong reduction of yki3SA-tumor growth in the midgut (Figure 2A), suggesting that MEK activation is crucial for yki3SA-tumor growth. Consistently, we observed a robust increase of pdERK in yki3SA-tumor gut cells (Figure 2C). Specific dERK knockdown in yki3SA tumors was sufficient to terminate tumor growth (Figure 2D and S1J–S1K). However, dERK gain of function alone in ISCs only slightly increased ISCs’ proliferation but failed to cause bloating/wasting (Figures S1L–S1N). Altogether, our results indicate that autonomous MEK activation in ISCs is required for yki3SA-tumor growth but is not sufficient to induce host wasting. To further investigate the role of MEK signaling in host tissues in the context of yki3SA-tumor growth, we fed yki3SA-tumor-bearing flies Tram with a lower dosage after tumor formation from day 4 (Figures S2A and S2B). 1, 10, and 100 μM Tram significantly decreased pdERK in both muscles and fat body of yki3SA-tumor-bearing flies in a dose-dependent manner (Figure S2D). 100 μM Tram still terminated, while 1 and 10 μM Tram hardly affected, yki3SA-tumor growth at day 8 (Figure S2C). Strikingly, 1 and 10 μM Tram potently alleviated wasting phenotypes, including abdomen bloating, muscle degeneration, lipid loss, and hyperglycemia in the presence of yki3SA tumors (Figures S2C–S2K). To validate the direct effect of Tram on host tissues, we treated isolated adult fat bodies from yki3SA-tumor-bearing flies with Tram in vitro and confirmed that Tram robustly suppressed yki3SA-tumor-induced lipolysis (Figure S1I). Similar to wasting-associated mortality of cancer patients (Fearon et al., 2013Fearon K. Arends J. Baracos V. Understanding the mechanisms and treatment options in cancer cachexia.Nat. Rev. Clin. Oncol. 2013; 10: 90-99Crossref PubMed Scopus (587) Google Scholar), yki3SA-tumor-bearing flies also exhibited a shortened lifespan, while it was surprisingly extended by 1 and 10 μM Tram (Figures S2L–S2M). Note that feeding 1 μM Tram did not affect yki3SA-tumor growth even at day 30 when most yki3SA-tumor-bearing flies died (Figure S2N). To further exclude the drug effect on yki3SA-gut tumors and evaluate the impact of MEK signaling in host tissues only, we generated drug-resistant yki3SA tumors by specifically overexpressing an active form of dERK (encoded by rlSEM) (esg-GAL4, tub-GAL80TS, UAS-GFP/UAS-rlSEM; UAS-yki3SA/+, referred to as “yki3SA+dERKSEM tumor”). Feeding 10 μM Tram simultaneously at yki3SA+dERKSEM tumor initiation from day 0 could no longer affect gut-tumor growth at day 8 (Figures 2E and 2F), while dramatically decreasing host MEK activation (Figure 2G). Strikingly, bloating/wasting phenotypes, including muscle defect, lipid loss, hyperglycemia, and mortality were significantly alleviated (Figures 2F–2J). Note that Tram administration in control flies (esg-GAL4, tub-GAL80TS, UAS-GFP/+) rarely affected wasting effects (Figures S3A and S3B). We also confirmed the anti-wasting effects of another MEK inhibitor, PD0325901 (PD), in flies bearing yki3SA+dERKSEM tumors (Figures S3C–S3E, albeit at a higher dose). Collectively, our results demonstrate that host MEK suppression is sufficient to improve yki3SA-tumor-induced wasting. We next tested whether the similar effects of MEK activation could be observed in mammalian wasting models. Conditioned medium from mouse LLC (Lewis lung carcinoma) cancer cells strongly induces lipid loss in adipocytes and myotube atrophy (Rohm et al., 2016Rohm M. Schäfer M. Laurent V. Üstünel B.E. Niopek K. Algire C. Hautzinger O. Sijmonsma T.P. Zota A. Medrikova D. et al.An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.Nat. Med. 2016; 22: 1120-1130Crossref PubMed Scopus (77) Google Scholar, Zhang et al., 2017Zhang G. Liu Z. Ding H. Miao H. Garcia J.M. Li Y.P. Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways.Sci. Rep. 2017; 7: 2273Crossref PubMed Scopus (54) Google Scholar). We found that LLC-conditioned medium activates MEK signaling in both cultured C2C12 myotubes and 3T3-L1 adipocytes after 15 min treatment (Figures S4A and S4F). Interestingly, LLC-conditioned medium robustly resulted in, while adding Tram significantly alleviated, MEK-associated induction of ubiquitination-related genes (UbC and USP19) and protein degradation, decrease of MHC level, and atrophy phenotype in C2C12 myotubes (Liu et al., 2011Liu Q. Xu W.G. Luo Y. Han F.F. Yao X.H. Yang T.Y. Zhang Y. Pi W.F. Guo X.J. Cigarette smoke-induced skeletal muscle atrophy is associated with up-regulation of USP-19 via p38 and ERK MAPKs.J. Cell. Biochem. 2011; 112: 2307-2316Crossref PubMed Scopus (49) Google Scholar, Zheng et al., 2010Zheng B. Ohkawa S. Li H. Roberts-Wilson T.K. Price S.R. FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy.FASEB J. 2010; 24: 2660-2669Crossref PubMed Scopus (97) Google Scholar) (Figures S4A–S4E). Similarly, LLC-conditioned medium potently enhanced, while adding Tram significantly hampered, lipolysis rate and TAG decline in differentiated 3T3-L1 adipocytes (Figures S4F–S4I). Thus, our results demonstrate that MEK activation also causes tumor-induced wasting in mammalian myotubes and adipocytes. We hypothesized that MEK non-autonomous regulation of host wasting is caused by secreted proteins from yki3SA-gut tumors. To identify such factors, we characterized the transcriptomic changes in yki3SA-tumor midguts using RNA-seq. Following statistical analysis, 2,211 genes were found to be significantly changed (fold change > 2) encompassing 1,659 up- and 552 down-regulated genes in yki3SA midguts (Figure 3A; Table S1). Among the 794 genes encoding secreted proteins annotated by GLAD Gene Ontology (Hu et al., 2015Hu Y. Comjean A. Perkins L.A. Perrimon N. Mohr S.E. GLAD: an online database of gene list annotation for Drosophila.J. Genomics. 2015; 3: 75-81Crossref PubMed Google Scholar), 92 were significantly up-regulated and 36 were down-regulated (Table S1). Genes encoding different trypsins were the most differentially regulated in yki3SA-tumor guts (Figure S3F, up). As flies bearing yki3SA tumors did not exhibit a digestion or absorption problem (Kwon et al., 2015Kwon Y. Song W. Droujinine I.A. Hu Y. Asara J.M. Perrimon N. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2.Dev. Cell. 2015; 33: 36-46Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar), we speculate that yki3SA tumors only change the composition of trypsin production but do not affect trypsin-associated nutrient absorption in the gut. Interestingly, the transcriptional levels of gut hormones, which are produced in enteroendocrine cells (EEs) (Reiher et al., 2011Reiher W. Shirras C. Kahnt J. Baumeister S. Isaac R.E. Wegener C. Peptidomics and peptide hormone processing in the Drosophila midgut.J. Proteome Res. 2011; 10: 1881-1892Crossref PubMed Scopus (77) Google Scholar, Song et al., 2017aSong W. Cheng D. Hong S. Sappe B. Hu Y. Wei N. Zhu C. O'Connor M.B. Pissios P. Perrimon N. Midgut-derived activin regulates glucagon-like action in the fat body and glycemic control.Cell Metab. 2017; 25: 386-399Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, Song et al., 2014Song W. Veenstra J.A. Perrimon N. Control of lipid metabolism by tachykinin in Drosophila.Cell Rep. 2014; 9: 40-47Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), were decreased in yki3SA midguts (Figure S3F, down). Immunostainings also revealed that EEs (Pros+ cells) were largely missing in yki3SA midguts (Figure S3G). We next asked whether yki3SA-gut tumors cause host wasting via loss of EEs and gut hormones, and overexpressed an active form of Notch (Nact) in ISCs to genetically suppress EE generation in the midgut (Takashima et al., 2011Takashima S. Adams K.L. Ortiz P.A. Ying C.T. Moridzadeh R. Younossi-Hartenstein A. Hartenstein V. Development of the Drosophila entero-endocrine lineage and its specification by the Notch signaling pathway.Dev. Biol. 2011; 353: 161-172Crossref PubMed Scopus (52) Google Scholar). Consistently, ISC overexpression of Nact potently eliminated EEs in the midgut (Figure S3G) but failed to affect bloating/wasting effects (Figure S3H). Nact overexpression slightly reduced survival rates of flies (Figure S3I), but the extent of decline was very marginal as compared to yki3SA-tumor-bearing flies. We next hypothesized that yki3SA-gut tumors cause host wasting via increasing the production of a cachectic ligand(s) such as ImpL2. We thus performed an RNAi screening of most up-regulated ligand-encoding genes in yki3SA tumors (Figure 3B). Interestingly, knockdown of 39 ligand-encoding genes (60 RNAi lines) in yki3SA-gut tumors still exhibited both tumor growth and abdomen bloating. However, knockdown of 17 ligand-encoding genes (24 RNAi lines) in yki3SA-gut tumors (referred to as Group “Tumor without Bloating”) diminished bloating without affecting tumor growth, suggesting that these ligands regulate tumor-induced wasting. Knockdown of 8 genes (11 RNAi lines) (referred to as Group “Non-tumor”) exhibited no tumor growth, suggesting that these ligands are essential for yki-induced tumorigenesis (Figure 3C; Table S2). Among the established MEK-activating ligands that are induced in yki3SA-tumor guts (Figures 3D and S3J), only Pvf1 knockdown in yki3SA tumors potently abolished the bloating phenotypes without perturbing yki3SA-tumor growth, while only vn knockdown terminated yki3SA-tumor growth (Figures 3C and 3E). Consistently, blockade of vn/Egfr signaling via knockdown of Egfr or its downstream Ras85D, but not blockade of Pvf1/Pvr signaling via overexpressing a dominant negative Pvr (Pvr.DN), terminated yki3SA-tumor growth (Figure 3F). These results indicate that yki3SA-tumor cells produce vn to activate autonomous Egfr/MEK signaling and promote growth. We next confirmed Pvf1 expression in the ISCs (Figure 3G) and found that Pvf1 knockdown in yki3SA tumors suppressed pdERK levels significantly in the fat body and moderately in muscles and subsequently improved systemic wasting, including TAG decline, trehalose elevation, and muscle defects, in tumor-bearing flies (Figures 3H–3K). We also generated yki3SA-tumors in Pvf1-null mutant flies (Wu et al., 2009Wu Y. Brock A.R. Wang Y. Fujitani K. Ueda R. Galko M.J. A blood-borne PDGF/VEGF-like ligand initiates wound-induced epidermal cell migration in Drosophila larvae.Curr. Biol. 2009; 19: 1473-1477Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) and confirmed that systemic removal of Pvf1 also significantly alleviated the wasting effects in host tissues without perturbing yki3SA-tumor growth (Figures 3M and 3N). Despite restoration of host wasting, Pvf1 knockdown in yki3SA tumors failed to extend longevity of tumor-bearing flies (Figure 3L), indicating that tumor-associated mortality involves other processes than host energy regulation. Since vn knockdown diminished tumor growth, systemic wasting effects were not observed in flies bearing yki3SA tumors with vn RNAi (Figures 3K and 3L). We further validated the autonomous effects of Pvr/MEK signaling by overexpressing an active form of Pvr (Pvr.λ) in the host tissues. Consistently, Pvr gain of function in the fat body resulted in MEK activation, lipid loss, and trehalose elevation (Figures 4A–4C ), while in muscle, it potently caused climbing defects (Figures 4D and 4E). To mimic Pvf1 induction in yki3SA-tumor-bearing midgut, we further overexpressed Pvf1 in wild-type enterocytes and found MEK activation in both muscle and fat body and wasting effects, even though no obvious abdomen bloating was observed (Figures 4F and 4G). Note that Tram administration in flies bearing yki3SA+dERKSEM tumors failed to affect Pvf1 levels in the midgut (Figures S3J and S3K), suggesting that Tram suppresses host MEK signaling independent of midgut Pvf1. Collectively, our results demonstrate that yki3SA-gut tumors produce Pvf1 to non-autonomously enhance Pvr/MEK signaling in host tissues and cause wasting. We previously showed that yki3SA-tumor-derived ImpL2 contributes to host wasting (Kwon et al., 2015Kwon Y. Song W. Droujinine I.A. Hu Y. Asara J.M. Perrimon N. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2.Dev. Cell. 2015; 33: 36-46Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). Thus, we wondered whether ImpL2 and Pvf1 are independent regulators. We first examined whether tumor-derived ImpL2 affects host MEK signaling and found that ImpL2 knockdown in yki3SA tumors failed to suppress host pdERK (Figure 4I). In addition, MEK suppression does not impinge on tumor-derived ImpL2 to affect wasting, as administration of 10 μM Tram in flies bearing yki3SA+dERKSEM tumors failed to affect tumor ImpL2 production, brain ILPs levels, as well as feeding behavior (Figures S3K–S3M). Similarly, Pvf1 removal in yki3SA-gut tumors also barely affected tumor ImpL2 production (Figure S3N). To examine a potential crosstalk between Pvf1 and ImpL2, we knocked down both Pvf1 and ImpL2 in yki3SA tumors. Surprisingly, as compared to knockdown of either Pvf1 or ImpL2, double knockdown of these two ligands in yki3SA tumors further alleviated host wasting, including bloating rates, lipid loss, as well as hyperglycemia, without affecting tumor growth (Figures 4J and 4K). Taken together, our results demonstrate that yki3SA-tumor-derived Pvf1 and ImpL2 are independent regulators of host wasting. Lipid loss and protein degradation-associated muscle wasting are two major features of tumor-induced host wasting in mammals (Fearon et al., 2013Fearon K. Arends J. Baracos V. Understanding the mechanisms and treatment options in cancer cachexia.Nat. Rev. Clin. Oncol. 2013; 10: 90-99Crossref PubMed Scopus (587) Google Scholar). We observe similar outcomes in yki3SA-tumor-bearing flies and show that the MEK/ERK pathway acts as a critical pathogenic factor. Although the molecular mechanisms of MEK action in fly are unknown, our results are reminiscent of some mammalian studies. For example, MEK signaling was found to regulate ubiquitination-associated proteolysis in mouse myotubes and promote lipid mobilization in mammalian adipocytes (Hong et al., 2018Hong S. Song W. Zushin P.H. Liu B. Jedrychowski M.P. Mina A.I. Deng Z. Cabarkapa D. Hall J.A. Palmer C.J. et al.Phosphorylation of beta-3 adrenergic receptor at serine 247 by ERK MAP kinase drives lipolysis in obese adipocytes.Mol. Metab. 2018; 12: 25-38Crossref PubMed Scopus (43) Google Scholar, Zheng et al., 2010Zheng B. Ohkawa S. Li H. Roberts-Wilson T.K. Price S.R. FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy.FASEB J. 2010; 24: 2660-2669Crossref PubMed Scopus (97) Google Scholar). We further confirmed similar MEK regulation in mammalian wasting models. Therefore, our study reveals that host MEK signaling plays a conserved role in tumor-induced wasting, including muscle wasting and lipid loss. The mechanism underlying the regulation of MEK signaling in tumor-induced host wasting is poorly understood. Here, we identified the secreted protein Pvf1 as a tumor-derived factor activating host MEK signaling. Pvr, the Pvf1 receptor, is expressed in both fat body and muscle (Kwon et al., 2015Kwon Y. Song W. Droujinine I.A. Hu Y. Asara J.M. Perrimon N. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2.Dev. Cell. 2015; 33: 36-46Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, Zheng et al., 2017Zheng H. Wang X. Guo P. Ge W. Yan Q. Gao W. Xi Y. Yang X. Premature remodeling of fat body and fat mobilization triggered by platelet-derived growth factor/VEGF receptor in Drosophila.FASEB J. 2017; 31: 1964-1975Crossref PubMed Scopus (8) Google Scholar). Activation of Pvf/Pvr signaling by overexpressing an active form of Pvr in the muscle and fat body is sufficient to cause muscle wasting and lipid loss, respectively. Reducing Pvf1 production in yki3SA-gut tumors decreased host MEK signaling and robustly alleviated wasting effects, while Pvf1 overexpression in wild-type midgut enterocytes somehow mimicked tumor-induced wasting effects, confirming that yki3SA-gut tumor-derived Pvf1 non-autonomously promotes host MEK signaling and wasting. Note that as compared to pharmaceutical MEK inhibition in host tissues, Pvf1 removal from yki3SA-gut tumors fails to prolong survival suggesting that systemic regulation of survival is more complicated than energy wasting in the context of tumor growth. We speculate that Pvf1/Pvr/MEK signaling is missing from some host tissues and that additional MEK-activating ligands produced either directly from yki3SA tumors or indirectly in host tissues contribute to mortality. Autonomous MEK activation in yki3SA-gut tumors is required for tumor growth. We demonstrate that only vn, a MEK-activating ligand essential for ISC proliferation (Xu et al., 2011Xu N. Wang S.Q. Tan D. Gao Y. Lin G. Xi R. EGFR, Wingless and JAK/STAT signaling cooperatively maintain Drosophila intestinal stem cells.Dev. Biol. 2011; 354: 31-43Crossref PubMed Scopus (159) Google Scholar), is critical for yki3SA-gut tumor growth by activating Egfr/MEK signaling. Altogether, we propose a dual-MEK regulatory model whereby yki3SA-gut tumors produce vn to autonomously promote self-growth, and Pvf1 to non-autonomously trigger Pvr/MEK signaling in host tissues and cause wasting (Figure 4H). We have" @default.
• W2909969237 created "2019-01-25" @default.
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• W2909969237 date "2019-01-01" @default.
• W2909969237 modified "2023-10-11" @default.
• W2909969237 title "Tumor-Derived Ligands Trigger Tumor Growth and Host Wasting via Differential MEK Activation" @default.
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