title: Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting.
abstract: Tumors kill patients not only through well-characterized perturbations to their local environment but also through poorly understood pathophysiological interactions with distant tissues. Here, we use a Drosophila tumor model to investigate the elusive mechanisms underlying such long-range interactions. Transplantation of tumors into adults induces robust wasting of adipose, muscle, and gonadal tissues that are distant from the tumor, phenotypes that resemble the cancer cachexia seen in human patients. Notably, malignant, but not benign, tumors induce peripheral wasting. We identify the insulin growth factor binding protein (IGFBP) homolog ImpL2, an antagonist of insulin signaling, as a secreted factor mediating wasting. ImpL2 is sufficient to drive tissue loss, and insulin activity is reduced in peripheral tissues of tumor-bearing hosts. Importantly, knocking down ImpL2, specifically in the tumor, ameliorates wasting phenotypes. We propose that the tumor-secreted IGFBP creates insulin resistance in distant tissues, thus driving a systemic wasting response.
authors: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3200, USA.
authors: Alejandra
authors: A
authors: Figueroa-Clarevega
authors: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3200, USA. Electronic address: bilder@berkeley.edu.
authors: David
authors: D
authors: Bilder
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007328:Insulin / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D029721:Drosophila Proteins; D007328:Insulin; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; D000255:Adenosine Triphosphate