{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:59:57Z","timestamp":1791874797636,"version":"4.3.4"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["91957118"],"award-info":[{"award-number":["91957118"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32350013"],"award-info":[{"award-number":["32350013"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People&apos;s Republic of China","doi-asserted-by":"publisher","award":["2021YFC2700700"],"award-info":[{"award-number":["2021YFC2700700"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Discov"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tumor\u2012host interaction plays a critical role in malignant tumor-induced organ wasting across multiple species. Despite known regulation of regional wasting of individual peripheral organs by tumors, whether and how tumors utilize critical host catabolic hormone(s) to simultaneously induce systemic host wasting, is largely unknown. Using the conserved yki\n                    <jats:sup>3SA<\/jats:sup>\n                    -tumor model in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    , we discovered that tumors increase the production of adipokinetic hormone (Akh), a glucagon-like catabolic hormone, to cause systemic host wasting, including muscle dysfunction, lipid loss, hyperglycemia, and ovary atrophy. We next integrated RNAi screening and Gal4-LexA dual expression system to show that yki\n                    <jats:sup>3SA<\/jats:sup>\n                    -gut tumors secrete Pvf1 to remotely activate its receptor Pvr in Akh-producing cells (APCs), ultimately promoting Akh production. The underlying molecular mechanisms involved the Pvf1-Pvr axis that triggers Mmp2-dependent ECM remodeling of APCs and enhances innervation from the excitatory cholinergic neurons. Interestingly, we also confirmed the similar mechanisms governing tumor-induced glucagon release and organ wasting in mammals. Blockade of either glucagon or PDGFR (homolog of Pvr) action efficiently ameliorated organ wasting in the presence of malignant tumors. Therefore, our results demonstrate that tumors remotely promote neural-associated Akh\/glucagon production via Pvf1-Pvr axis to cause systemic host wasting.\n                  <\/jats:p>","DOI":"10.1038\/s41421-024-00762-0","type":"journal-article","created":{"date-parts":[[2025,2,9]],"date-time":"2025-02-09T20:02:36Z","timestamp":1739131356000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A tumor-secreted protein utilizes glucagon release to cause host wasting"],"prefix":"10.1038","volume":"11","author":[{"given":"Guangming","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingge","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-2335","authenticated-orcid":false,"given":"Huiwen","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peixuan","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Rushworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7007-5281","authenticated-orcid":false,"given":"Wei","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"762_CR1","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/nrc3829","volume":"14","author":"JM Argiles","year":"2014","unstructured":"Argiles, J. M., Busquets, S., Stemmler, B. & Lopez-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754\u2013762 (2014).","journal-title":"Nat. Rev. Cancer"},{"key":"762_CR2","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1139\/apnm-2013-0369","volume":"39","author":"S Chevalier","year":"2014","unstructured":"Chevalier, S. & Farsijani, S. Cancer cachexia and diabetes: similarities in metabolic alterations and possible treatment. Appl. Physiol. Nutr. Metab. 39, 643\u2013653 (2014).","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"762_CR3","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1038\/bjc.2014.90","volume":"110","author":"CS Roxburgh","year":"2014","unstructured":"Roxburgh, C. S. & McMillan, D. C. Cancer and systemic inflammation: treat the tumour and treat the host. Br. J. Cancer 110, 1409\u20131412 (2014).","journal-title":"Br. J. Cancer"},{"key":"762_CR4","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/mt.2014.221","volume":"23","author":"JL Chen","year":"2015","unstructured":"Chen, J. L. et al. Development of novel activin-targeted therapeutics. Mol. Ther. 23, 434\u2013444 (2015).","journal-title":"Mol. Ther."},{"key":"762_CR5","doi-asserted-by":"publisher","first-page":"3999","DOI":"10.1158\/1078-0432.CCR-16-0495","volume":"22","author":"Y Miyamoto","year":"2016","unstructured":"Miyamoto, Y., Hanna, D. L., Zhang, W., Baba, H. & Lenz, H. J. Molecular pathways: cachexia signaling-A targeted approach to cancer treatment. Clin. Cancer Res. 22, 3999\u20134004 (2016).","journal-title":"Clin. Cancer Res."},{"key":"762_CR6","doi-asserted-by":"publisher","first-page":"19976","DOI":"10.1074\/jbc.M115.638411","volume":"290","author":"DN Seto","year":"2015","unstructured":"Seto, D. N., Kandarian, S. C. & Jackman, R. W. A key role for leukemia inhibitory factor in C26 cancer cachexia. J. Biol. Chem. 290, 19976\u201319986 (2015).","journal-title":"J. Biol. Chem."},{"key":"762_CR7","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.cell.2010.07.011","volume":"142","author":"X Zhou","year":"2010","unstructured":"Zhou, X. et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531\u2013543 (2010).","journal-title":"Cell"},{"key":"762_CR8","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nature13528","volume":"513","author":"S Kir","year":"2014","unstructured":"Kir, S. et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513, 100\u2013104 (2014).","journal-title":"Nature"},{"key":"762_CR9","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/s41586-023-06047-y","volume":"617","author":"SN Bilgic","year":"2023","unstructured":"Bilgic, S. N. et al. EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia. Nature 617, 827\u2013834 (2023).","journal-title":"Nature"},{"key":"762_CR10","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1152\/japplphysiol.01026.2004","volume":"98","author":"F Haddad","year":"2005","unstructured":"Haddad, F., Zaldivar, F., Cooper, D. M. & Adams, G. R. IL-6-induced skeletal muscle atrophy. J. Appl. Physiol. (1985) 98, 911\u2013917 (2005).","journal-title":"J. Appl. Physiol. (1985)"},{"key":"762_CR11","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1002\/ijc.33418","volume":"148","author":"TD Nguyen","year":"2021","unstructured":"Nguyen, T. D., Miyatake, Y., Yoshida, T., Kawahara, H. & Hanayama, R. Tumor-secreted proliferin-1 regulates adipogenesis and lipolysis in cachexia. Int. J. Cancer 148, 1982\u20131992 (2021).","journal-title":"Int. J. Cancer"},{"key":"762_CR12","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109553","volume":"36","author":"G Ding","year":"2021","unstructured":"Ding, G. et al. Coordination of tumor growth and host wasting by tumor-derived Upd3. Cell Rep. 36, 109553 (2021).","journal-title":"Cell Rep."},{"key":"762_CR13","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.devcel.2015.02.012","volume":"33","author":"Y Kwon","year":"2015","unstructured":"Kwon, Y. et al. Systemic organ wasting induced by localized expression of the secreted insulin\/IGF antagonist ImpL2. Dev. Cell 33, 36\u201346 (2015).","journal-title":"Dev. Cell"},{"key":"762_CR14","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.devcel.2018.12.003","volume":"48","author":"W Song","year":"2019","unstructured":"Song, W. et al. Tumor-derived ligands trigger tumor growth and host wasting via differential MEK cctivation. Dev. Cell 48, 277\u2013286.e6 (2019).","journal-title":"Dev. Cell"},{"key":"762_CR15","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.devcel.2015.03.001","volume":"33","author":"A Figueroa-Clarevega","year":"2015","unstructured":"Figueroa-Clarevega, A. & Bilder, D. Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev. Cell 33, 47\u201355 (2015).","journal-title":"Dev. Cell"},{"key":"762_CR16","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1002\/jcsm.12692","volume":"12","author":"J Dong","year":"2021","unstructured":"Dong, J. et al. Serum insulin-like growth factor binding protein 2 levels as biomarker for pancreatic ductal adenocarcinoma-associated malnutrition and muscle wasting. J. Cachexia Sarcopenia Muscle 12, 704\u2013716 (2021).","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"762_CR17","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1002\/jcsm.12346","volume":"9","author":"SC Kandarian","year":"2018","unstructured":"Kandarian, S. C. et al. Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice. J. Cachexia Sarcopenia Muscle 9, 1109\u20131120 (2018).","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"762_CR18","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.cmet.2016.10.010","volume":"24","author":"TR Flint","year":"2016","unstructured":"Flint, T. R. et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24, 672\u2013684 (2016).","journal-title":"Cell Metab."},{"key":"762_CR19","doi-asserted-by":"publisher","first-page":"2664","DOI":"10.1016\/j.devcel.2021.08.008","volume":"56","author":"W Lodge","year":"2021","unstructured":"Lodge, W. et al. Tumor-derived MMPs regulate cachexia in a Drosophila cancer model. Dev. Cell 56, 2664\u20132680.e6 (2021).","journal-title":"Dev. Cell"},{"key":"762_CR20","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1038\/nature02897","volume":"431","author":"SK Kim","year":"2004","unstructured":"Kim, S. K. & Rulifson, E. J. Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells. Nature 431, 316\u2013320 (2004).","journal-title":"Nature"},{"key":"762_CR21","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1534\/genetics.167.1.311","volume":"167","author":"G Lee","year":"2004","unstructured":"Lee, G. & Park, J. H. Hemolymph sugar homeostasis and starvation-induced hyperactivity affected by genetic manipulations of the adipokinetic hormone-encoding gene in Drosophila melanogaster. Genetics 167, 311\u2013323 (2004).","journal-title":"Genetics"},{"key":"762_CR22","doi-asserted-by":"publisher","first-page":"5407","DOI":"10.3390\/ijms20215407","volume":"20","author":"M Kleinert","year":"2019","unstructured":"Kleinert, M., Sachs, S., Habegger, K. M., Hofmann, S. M. & Muller, T. D. Glucagon regulation of energy expenditure. Int. J. Mol. Sci. 20, 5407 (2019).","journal-title":"Int. J. Mol. Sci"},{"key":"762_CR23","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1210\/en.2011-1979","volume":"153","author":"BJ Jones","year":"2012","unstructured":"Jones, B. J., Tan, T. & Bloom, S. R. Minireview: glucagon in stress and energy homeostasis. Endocrinology 153, 1049\u20131054 (2012).","journal-title":"Endocrinology"},{"key":"762_CR24","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.cmet.2017.01.002","volume":"25","author":"W Song","year":"2017","unstructured":"Song, W. et al. Midgut-derived activin regulates glucagon-like action in the fat body and glycemic control. Cell Metab. 25, 386\u2013399 (2017).","journal-title":"Cell Metab."},{"key":"762_CR25","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.jgg.2014.03.005","volume":"41","author":"J Baumbach","year":"2014","unstructured":"Baumbach, J., Xu, Y., Hehlert, P. & Kuhnlein, R. P. Galphaq, Ggamma1 and Plc21C control Drosophila body fat storage. J. Genet. Genomics 41, 283\u2013292 (2014).","journal-title":"J. Genet. Genomics"},{"key":"762_CR26","doi-asserted-by":"publisher","first-page":"e137","DOI":"10.1371\/journal.pbio.0050137","volume":"5","author":"S Gronke","year":"2007","unstructured":"Gronke, S. et al. Dual lipolytic control of body fat storage and mobilization in Drosophila. PLoS Biol. 5, e137 (2007).","journal-title":"PLoS Biol."},{"key":"762_CR27","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1093\/icb\/icp019","volume":"49","author":"MW Lorenz","year":"2009","unstructured":"Lorenz, M. W. & Gade, G. Hormonal regulation of energy metabolism in insects as a driving force for performance. Integr. Comp. Biol. 49, 380\u2013392 (2009).","journal-title":"Integr. Comp. Biol."},{"key":"762_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113200","volume":"42","author":"J Li","year":"2023","unstructured":"Li, J. et al. Peroxisomal ERK mediates Akh\/glucagon action and glycemic control. Cell Rep. 42, 113200 (2023).","journal-title":"Cell Rep."},{"key":"762_CR29","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1016\/j.cub.2017.06.004","volume":"27","author":"X Zhao","year":"2017","unstructured":"Zhao, X. & Karpac, J. Muscle directs diurnal energy homeostasis through a myokine-dependent hormone module in Drosophila. Curr. Biol. 27, 1941\u20131955.e6 (2017).","journal-title":"Curr. Biol."},{"key":"762_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25146-w","volume":"12","author":"Y Yoshinari","year":"2021","unstructured":"Yoshinari, Y. et al. The sugar-responsive enteroendocrine neuropeptide F regulates lipid metabolism through glucagon-like and insulin-like hormones in Drosophila melanogaster. Nat. Commun. 12, 4818 (2021).","journal-title":"Nat. Commun."},{"key":"762_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/srep11680","volume":"5","author":"JL Hentze","year":"2015","unstructured":"Hentze, J. L., Carlsson, M. A., Kondo, S., Nassel, D. R. & Rewitz, K. F. The neuropeptide allatostatin A regulates metabolism and feeding decisions in Drosophila. Sci. Rep. 5, 11680 (2015).","journal-title":"Sci. Rep."},{"key":"762_CR32","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41421-023-00541-3","volume":"9","author":"Y Li","year":"2023","unstructured":"Li, Y. et al. Gut AstA mediates sleep deprivation-induced energy wasting in Drosophila. Cell Discov. 9, 49 (2023).","journal-title":"Cell Discov."},{"key":"762_CR33","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.cmet.2018.09.021","volume":"29","author":"A Scopelliti","year":"2019","unstructured":"Scopelliti, A. et al. A neuronal relay mediates a nutrient responsive Gut\/Fat body axis regulating energy homeostasis in adult Drosophila. Cell Metab. 29, 269\u2013284 e210 (2019).","journal-title":"Cell Metab."},{"key":"762_CR34","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/s41586-019-1675-4","volume":"574","author":"Y Oh","year":"2019","unstructured":"Oh, Y. et al. A glucose-sensing neuron pair regulates insulin and glucagon in Drosophila. Nature 574, 559\u2013564 (2019).","journal-title":"Nature"},{"key":"762_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25445-2","volume":"12","author":"T Koyama","year":"2021","unstructured":"Koyama, T. et al. A nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila. Nat. Commun. 12, 5178 (2021).","journal-title":"Nat. Commun."},{"key":"762_CR36","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.cmet.2008.02.012","volume":"7","author":"S Buch","year":"2008","unstructured":"Buch, S., Melcher, C., Bauer, M., Katzenberger, J. & Pankratz, M. J. Opposing effects of dietary protein and sugar regulate a transcriptional target of Drosophila insulin-like peptide signaling. Cell Metab. 7, 321\u2013332 (2008).","journal-title":"Cell Metab."},{"key":"762_CR37","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1534\/genetics.115.178897","volume":"201","author":"M Galikova","year":"2015","unstructured":"Galikova, M. et al. Energy homeostasis control in Drosophila adipokinetic hormone mutants. Genetics 201, 665\u2013683 (2015).","journal-title":"Genetics"},{"key":"762_CR38","doi-asserted-by":"publisher","first-page":"eabk2432","DOI":"10.1126\/science.abk2432","volume":"375","author":"H Li","year":"2022","unstructured":"Li, H. et al. Fly cell atlas: a single-nucleus transcriptomic atlas of the adult fruit fly. Science 375, eabk2432 (2022).","journal-title":"Science"},{"key":"762_CR39","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1016\/j.immuni.2022.07.022","volume":"55","author":"Y Chen","year":"2022","unstructured":"Chen, Y. et al. Renal NF-kappaB activation impairs uric acid homeostasis to promote tumor-associated mortality independent of wasting. Immunity 55, 1594\u20131608.e6 (2022).","journal-title":"Immunity"},{"key":"762_CR40","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/s41586-023-06833-8","volume":"624","author":"W Xu","year":"2023","unstructured":"Xu, W., Li, G., Chen, Y., Ye, X. & Song, W. A novel antidiuretic hormone governs tumour-induced renal dysfunction. Nature 624, 425\u2013432 (2023).","journal-title":"Nature"},{"key":"762_CR41","doi-asserted-by":"publisher","first-page":"a009050","DOI":"10.1101\/cshperspect.a009050","volume":"5","author":"R Sopko","year":"2013","unstructured":"Sopko, R. & Perrimon, N. Receptor tyrosine kinases in Drosophila development. Cold Spring Harb. Perspect. Biol. 5, a009050 (2013).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"762_CR42","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.1096\/fj.201601127R","volume":"31","author":"H Zheng","year":"2017","unstructured":"Zheng, H. et al. Premature remodeling of fat body and fat mobilization triggered by platelet-derived growth factor\/VEGF receptor in Drosophila. FASEB J. 31, 1964\u20131975 (2017).","journal-title":"FASEB J."},{"key":"762_CR43","doi-asserted-by":"publisher","first-page":"e48857","DOI":"10.7554\/eLife.48857","volume":"8","author":"J Sauerwald","year":"2019","unstructured":"Sauerwald, J., Backer, W., Matzat, T., Schnorrer, F. & Luschnig, S. Matrix metalloproteinase 1 modulates invasive behavior of tracheal branches during entry into Drosophila flight muscles. Elife 8, e48857 (2019).","journal-title":"Elife"},{"key":"762_CR44","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S1534-5807(02)00400-8","volume":"4","author":"A Page-McCaw","year":"2003","unstructured":"Page-McCaw, A., Serano, J., Sante, J. M. & Rubin, G. M. Drosophila matrix metalloproteinases are required for tissue remodeling, but not embryonic development. Dev. Cell 4, 95\u2013106 (2003).","journal-title":"Dev. Cell"},{"key":"762_CR45","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3389\/fnana.2018.00040","volume":"12","author":"M Ferrer-Ferrer","year":"2018","unstructured":"Ferrer-Ferrer, M. & Dityatev, A. Shaping synapses by the neural extracellular matrix. Front. Neuroanat. 12, 40 (2018).","journal-title":"Front. Neuroanat."},{"key":"762_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/srep07535","volume":"4","author":"Q Jia","year":"2014","unstructured":"Jia, Q., Liu, Y., Liu, H. & Li, S. Mmp1 and Mmp2 cooperatively induce Drosophila fat body cell dissociation with distinct roles. Sci. Rep. 4, 7535 (2014).","journal-title":"Sci. Rep."},{"key":"762_CR47","doi-asserted-by":"publisher","first-page":"20553","DOI":"10.1073\/pnas.1010198107","volume":"107","author":"LJ Nicolai","year":"2010","unstructured":"Nicolai, L. J. et al. Genetically encoded dendritic marker sheds light on neuronal connectivity in Drosophila. Proc. Natl. Acad. Sci. USA 107, 20553\u201320558 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"762_CR48","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1021\/acschemneuro.7b00456","volume":"9","author":"M Shin","year":"2018","unstructured":"Shin, M., Copeland, J. M. & Venton, B. J. Drosophila as a model system for neurotransmitter measurements. ACS Chem. Neurosci. 9, 1872\u20131883 (2018).","journal-title":"ACS Chem. Neurosci."},{"key":"762_CR49","doi-asserted-by":"publisher","first-page":"e2318760121","DOI":"10.1073\/pnas.2318760121","volume":"121","author":"H Zhu","year":"2024","unstructured":"Zhu, H., Ludington, W. B. & Spradling, A. C. Cellular and molecular organization of the Drosophila foregut. Proc. Natl. Acad. Sci. USA 121, e2318760121 (2024).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"762_CR50","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3389\/neuro.02.011.2009","volume":"2","author":"J Kasuya","year":"2009","unstructured":"Kasuya, J., Ishimoto, H. & Kitamoto, T. Neuronal mechanisms of learning and memory revealed by spatial and temporal suppression of neurotransmission using shibire, a temperature-sensitive dynamin mutant gene in Drosophila melanogaster. Front. Mol. Neurosci. 2, 11 (2009).","journal-title":"Front. Mol. Neurosci."},{"key":"762_CR51","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1634\/theoncologist.2018-0266","volume":"24","author":"AE Hendifar","year":"2019","unstructured":"Hendifar, A. E. et al. Pancreas cancer-associated weight loss. Oncologist 24, 691\u2013701 (2019).","journal-title":"Oncologist"},{"key":"762_CR52","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.lfs.2019.04.041","volume":"227","author":"B Yu","year":"2019","unstructured":"Yu, B. et al. Abnormality of hepatic triglyceride metabolism in Apc(Min\/+) mice with colon cancer cachexia. Life Sci. 227, 201\u2013211 (2019).","journal-title":"Life Sci."},{"key":"762_CR53","doi-asserted-by":"publisher","first-page":"R393","DOI":"10.1152\/ajpregu.00716.2007","volume":"294","author":"KA Baltgalvis","year":"2008","unstructured":"Baltgalvis, K. A. et al. Interleukin-6 and cachexia in ApcMin\/+ mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R393\u2013R401 (2008).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"762_CR54","doi-asserted-by":"publisher","first-page":"413","DOI":"10.3389\/fphys.2019.00413","volume":"10","author":"KD Galsgaard","year":"2019","unstructured":"Galsgaard, K. D., Pedersen, J., Knop, F. K., Holst, J. J. & Wewer Albrechtsen, N. J. Glucagon receptor signaling and lipid metabolism. Front. Physiol. 10, 413 (2019).","journal-title":"Front. Physiol."},{"key":"762_CR55","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.peptides.2017.11.013","volume":"100","author":"RV Scott","year":"2018","unstructured":"Scott, R. V. & Bloom, S. R. Problem or solution: the strange story of glucagon. Peptides 100, 36\u201341 (2018).","journal-title":"Peptides"},{"key":"762_CR56","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-01912-0","volume":"11","author":"CE Hinds","year":"2021","unstructured":"Hinds, C. E. et al. A glucagon analogue decreases body weight in mice via signalling in the liver. Sci. Rep. 11, 22577 (2021).","journal-title":"Sci. Rep."},{"key":"762_CR57","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/s42255-021-00369-9","volume":"3","author":"JG Okun","year":"2021","unstructured":"Okun, J. G. et al. Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes. Nat. Metab. 3, 394\u2013409 (2021).","journal-title":"Nat. Metab."},{"key":"762_CR58","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1097\/MCC.0000000000000509","volume":"24","author":"SE Thiessen","year":"2018","unstructured":"Thiessen, S. E., Gunst, J. & Van den Berghe, G. Role of glucagon in protein catabolism. Curr. Opin. Crit. Care 24, 228\u2013234 (2018).","journal-title":"Curr. Opin. Crit. Care"},{"key":"762_CR59","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.2337\/diabetes.53.7.1714","volume":"53","author":"A Duttaroy","year":"2004","unstructured":"Duttaroy, A. et al. Muscarinic stimulation of pancreatic insulin and glucagon release is abolished in m3 muscarinic acetylcholine receptor-deficient mice. Diabetes 53, 1714\u20131720 (2004).","journal-title":"Diabetes"},{"key":"762_CR60","doi-asserted-by":"publisher","first-page":"188","DOI":"10.3390\/ijms21010188","volume":"21","author":"S Mele","year":"2019","unstructured":"Mele, S. & Johnson, T. K. Receptor tyrosine kinases in development: insights from Drosophila. Int. J. Mol. Sci. 21, 188 (2019).","journal-title":"Int. J. Mol. Sci"},{"key":"762_CR61","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-620","volume":"15","author":"C Benner","year":"2014","unstructured":"Benner, C. et al. The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15, 620 (2014).","journal-title":"BMC Genomics"},{"key":"762_CR62","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1158\/1541-7786.MCR-07-0232","volume":"5","author":"K Yekkala","year":"2007","unstructured":"Yekkala, K. & Baudino, T. A. Inhibition of intestinal polyposis with reduced angiogenesis in ApcMin\/+ mice due to decreases in c-Myc expression. Mol. Cancer Res. 5, 1296\u20131303 (2007).","journal-title":"Mol. Cancer Res."},{"key":"762_CR63","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.neo.2017.04.006","volume":"19","author":"A Jayakumar","year":"2017","unstructured":"Jayakumar, A. & Bothwell, A. L. M. Stat6 promotes intestinal tumorigenesis in a mouse model of adenomatous polyposis by expansion of MDSCs and inhibition of cytotoxic CD8 response. Neoplasia 19, 595\u2013605 (2017).","journal-title":"Neoplasia"},{"key":"762_CR64","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.1158\/0008-5472.CAN-08-3779","volume":"69","author":"B Sennino","year":"2009","unstructured":"Sennino, B. et al. Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors. Cancer Res. 69, 4527\u20134536 (2009).","journal-title":"Cancer Res."},{"key":"762_CR65","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-11-286","volume":"11","author":"NN Rahbari","year":"2011","unstructured":"Rahbari, N. N. et al. Expression and prognostic value of circulating angiogenic cytokines in pancreatic cancer. BMC Cancer 11, 286 (2011).","journal-title":"BMC Cancer"},{"key":"762_CR66","doi-asserted-by":"publisher","first-page":"2368","DOI":"10.1158\/0008-5472.CAN-09-3249","volume":"70","author":"S Rajamanickam","year":"2010","unstructured":"Rajamanickam, S., Velmurugan, B., Kaur, M., Singh, R. P. & Agarwal, R. Chemoprevention of intestinal tumorigenesis in APCmin\/+ mice by silibinin. Cancer Res. 70, 2368\u20132378 (2010).","journal-title":"Cancer Res."},{"key":"762_CR67","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.3892\/ol.2011.380","volume":"2","author":"MS Tsai","year":"2011","unstructured":"Tsai, M. S., Chang, C. C., Kuo, M. L. & Wu, Y. T. Vascular endothelial growth factor-A and changes in a tumor-bearing mouse model with Lewis lung cancer. Oncol. Lett. 2, 1143\u20131147 (2011).","journal-title":"Oncol. Lett."},{"key":"762_CR68","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.7150\/thno.37851","volume":"10","author":"M Tsioumpekou","year":"2020","unstructured":"Tsioumpekou, M. et al. Specific targeting of PDGFRbeta in the stroma inhibits growth and angiogenesis in tumors with high PDGF-BB expression. Theranostics 10, 1122\u20131135 (2020).","journal-title":"Theranostics"},{"key":"762_CR69","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1158\/0008-5472.166.65.1","volume":"65","author":"T Reichling","year":"2005","unstructured":"Reichling, T. et al. Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors. Cancer Res. 65, 166\u2013176 (2005).","journal-title":"Cancer Res."},{"key":"762_CR70","doi-asserted-by":"publisher","first-page":"e56969","DOI":"10.7554\/eLife.56969","volume":"9","author":"AC Ghosh","year":"2020","unstructured":"Ghosh, A. C. et al. Drosophila PDGF\/VEGF signaling from muscles to hepatocyte-like cells protectsagainst obesity. Elife 9, e56969 (2020).","journal-title":"Elife"},{"key":"762_CR71","doi-asserted-by":"publisher","first-page":"4076","DOI":"10.1016\/j.cub.2021.07.002","volume":"31","author":"D Pauls","year":"2021","unstructured":"Pauls, D. et al. Endocrine signals fine-tune daily activity patterns in Drosophila. Curr. Biol. 31, 4076\u20134087.e5 (2021).","journal-title":"Curr. Biol."},{"key":"762_CR72","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19490-6","volume":"11","author":"PA Just","year":"2020","unstructured":"Just, P. A. et al. Lkb1 suppresses amino acid-driven gluconeogenesis in the liver. Nat. Commun. 11, 6127 (2020).","journal-title":"Nat. Commun."},{"key":"762_CR73","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s12276-022-00752-w","volume":"54","author":"E Yeom","year":"2022","unstructured":"Yeom, E. & Yu, K. Understanding the molecular basis of anorexia and tissue wasting in cancer cachexia. Exp. Mol. Med. 54, 426\u2013432 (2022).","journal-title":"Exp. Mol. Med."},{"key":"762_CR74","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1111\/dom.12345","volume":"16","author":"E Gylfe","year":"2014","unstructured":"Gylfe, E. & Tengholm, A. Neurotransmitter control of islet hormone pulsatility. Diabetes Obes. Metab. 16, 102\u2013110 (2014).","journal-title":"Diabetes Obes. Metab."},{"key":"762_CR75","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05309-y","volume":"9","author":"Y Liu","year":"2018","unstructured":"Liu, Y. et al. Insulin\/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis. Nat. Commun. 9, 2751 (2018).","journal-title":"Nat. Commun."}],"container-title":["Cell Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41421-024-00762-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41421-024-00762-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41421-024-00762-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,9]],"date-time":"2025-02-09T20:02:39Z","timestamp":1739131359000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41421-024-00762-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,10]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["762"],"URL":"https:\/\/doi.org\/10.1038\/s41421-024-00762-0","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.10.24.619567","asserted-by":"object"}]},"ISSN":["2056-5968"],"issn-type":[{"value":"2056-5968","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,10]]},"assertion":[{"value":"18 May 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"11"}}