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.
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We thank members of the Vander Heiden and Wolpin laboratories for discussions and the Koch Institute Swanson Biotechnology Center, particularly the Animal Imaging and Preclinical Testing Facility, for technical assistance. Major funding for this work was provided by the Lustgarten Foundation to B.M.W. and M.G.V.H. L.V.D. was supported by NIH Ruth Kirschstein Fellowship (F32CA210421). A.B. was supported by P50CA127003 and the Robert T. and Judith B. Hale Fund for Pancreatic Cancer Research. A.M. was supported by F32CA213810. E.C.L. was supported by the Damon Runyon Cancer Research Foundation (DRG-2299-17). A.N.L. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation (DRG-2241-15). B.M.W was supported by Robert T. and Judith B. Hale Fund for Pancreatic Cancer Research, NIH/NCI (U01CA210171), Department of Defense (CA130288), Pancreatic Cancer Action Network, Stand Up To Cancer, Noble Effort Fund, Peter R. Leavitt Family Fund, Wexler Family Fund, and Promises for Purple. M.G.V.H. was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute, and acknowledges additional funding from Stand Up To Cancer, The Ludwig Center at MIT, the Koch Institute Frontier Awards, the MIT Center for Precision Cancer Medicine, and the NIH (R01CA168653, P30CA14051).
Nature thanks M. Löhr and the other anonymous reviewer(s) for their contribution to the peer review of this work.