Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue

Gunisha Sagar, Raghuwansh P. Sah, Naureen Javeed, Shamit K. Dutta, Thomas Christopher Smyrk, Julie S. Lau, Nino Giorgadze, Tamar Tchkonia, James L Kirkland, Suresh T Chari, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Background and objectives 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. Design 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. Results 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. Conclusions PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.

Original languageEnglish (US)
JournalGut
DOIs
StateAccepted/In press - Apr 28 2015

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Exosomes
Lipolysis
Pancreatic Neoplasms
Adipose Tissue
Adrenomedullin
Adipocytes
Adrenomedullin Receptors
Weight Loss
Caveolins
Sterol Esterase
Subcutaneous Fat
Mitogen-Activated Protein Kinase 1
Endocytosis
Glycerol
Neoplasms
Western Blotting

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Sagar, G., Sah, R. P., Javeed, N., Dutta, S. K., Smyrk, T. C., Lau, J. S., ... Mukhopadhyay, D. (Accepted/In press). Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. Gut. https://doi.org/10.1136/gutjnl-2014-308350

Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. / Sagar, Gunisha; Sah, Raghuwansh P.; Javeed, Naureen; Dutta, Shamit K.; Smyrk, Thomas Christopher; Lau, Julie S.; Giorgadze, Nino; Tchkonia, Tamar; Kirkland, James L; Chari, Suresh T; Mukhopadhyay, Debabrata.

In: Gut, 28.04.2015.

Research output: Contribution to journalArticle

Sagar, Gunisha ; Sah, Raghuwansh P. ; Javeed, Naureen ; Dutta, Shamit K. ; Smyrk, Thomas Christopher ; Lau, Julie S. ; Giorgadze, Nino ; Tchkonia, Tamar ; Kirkland, James L ; Chari, Suresh T ; Mukhopadhyay, Debabrata. / Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. In: Gut. 2015.
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abstract = "Background and objectives 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. Design 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. Results 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. Conclusions PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.",
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AU - Sagar, Gunisha

AU - Sah, Raghuwansh P.

AU - Javeed, Naureen

AU - Dutta, Shamit K.

AU - Smyrk, Thomas Christopher

AU - Lau, Julie S.

AU - Giorgadze, Nino

AU - Tchkonia, Tamar

AU - Kirkland, James L

AU - Chari, Suresh T

AU - Mukhopadhyay, Debabrata

PY - 2015/4/28

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N2 - Background and objectives 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. Design 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. Results 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. Conclusions PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.

AB - Background and objectives 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. Design 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. Results 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. Conclusions PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.

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