title: Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue.
abstract: New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumour-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesise that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC-exosomes as the mediator of this lipolysis.
  
  
  
  Exosomes from patient-derived cell lines and from plasma of patients with PC and non-PC controls were isolated and characterised. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink Assay was used to study AM and adrenomedullin receptor (ADMR) interaction in adipocytes treated with exosomes.
  
  
  
  In murine and human adipocytes, we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by ADMR blockade. AM interacted with its receptor on the adipocytes, activated p38 and extracellular signal-regulated (ERK1/2) mitogen-activated protein kinases and promoted lipolysis by phosphorylating hormone-sensitive lipase. PKH67-labelled PC-exosomes were readily internalised into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis.
  
  
  
  PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Gunisha
authors.initials: G
authors.lastname: Sagar
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Raghuwansh P
authors.initials: RP
authors.lastname: Sah
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Naureen
authors.initials: N
authors.lastname: Javeed
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Shamit K
authors.initials: SK
authors.lastname: Dutta
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Lau
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Nino
authors.initials: N
authors.lastname: Giorgadze
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Suresh T
authors.initials: ST
authors.lastname: Chari
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D053607:Adrenomedullin / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology; D055354:Exosomes / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D008066:Lipolysis; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D058265:Receptors, Adrenomedullin / Q000037:antagonists & inhibitors / Q000378:metabolism; D050151:Subcutaneous Fat / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D058265:Receptors, Adrenomedullin; D053607:Adrenomedullin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D005990:Glycerol
keywords: CANCER; PANCREAS; PANCREATIC CANCER