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Nature. 2018 Jun;558(7711):600-604. doi: 10.1038/s41586-018-0235-7. Epub 2018 Jun 20.

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Author information

1
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
2
Dana-Farber Cancer Institute, Boston, MA, USA.
3
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
4
Mayo Clinic, Rochester, MN, USA.
5
Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
6
University of California San Diego School of Medicine, La Jolla, CA, USA.
7
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
8
MD Anderson, Department of Radiation Oncology, Houston, TX, USA.
9
Stanford Cancer Institute, Stanford, CA, USA.
10
David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
11
Section of Hematology/Oncology, Boston University and Boston Medical Center, Boston, MA, USA.
12
Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
13
Dana-Farber Cancer Institute, Boston, MA, USA. bwolpin@partners.org.
14
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. mvh@mit.edu.
15
Dana-Farber Cancer Institute, Boston, MA, USA. mvh@mit.edu.
16
Broad Institute of MIT and Harvard University, Cambridge, MA, USA. mvh@mit.edu.

Abstract

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.

PMID:
29925948
PMCID:
PMC6112987
[Available on 2018-12-20]
DOI:
10.1038/s41586-018-0235-7

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