Altered exocrine function can drive adipose wasting in early pancreatic cancer

Laura V. Danai, Ana Babic, Michael H. Rosenthal, Emily A. Dennstedt, Alexander Muir, Evan C. Lien, Jared R. Mayers, Karen Tai, Allison N. Lau, Paul Jones-Sali, Carla M. Prado, Gloria M. Petersen, Naoki Takahashi, Motokazu Sugimoto, Jen Jen Yeh, Nicole Lopez, Nabeel Bardeesy, Carlos Fernandez-del Castillo, Andrew S. Liss, Albert C. Koong, Justin Bui, Chen Yuan, Marisa W. Welch, Lauren K. Brais, Matthew H. Kulke, Courtney Dennis, Clary B. Clish, Brian M. Wolpin () and Matthew G. Vander Heiden ()
Additional contact information
Laura V. Danai: Massachusetts Institute of Technology
Ana Babic: Dana-Farber Cancer Institute
Michael H. Rosenthal: Dana-Farber Cancer Institute
Emily A. Dennstedt: Massachusetts Institute of Technology
Alexander Muir: Massachusetts Institute of Technology
Evan C. Lien: Massachusetts Institute of Technology
Jared R. Mayers: Massachusetts Institute of Technology
Karen Tai: Massachusetts Institute of Technology
Allison N. Lau: Massachusetts Institute of Technology
Paul Jones-Sali: Massachusetts Institute of Technology
Carla M. Prado: University of Alberta
Gloria M. Petersen: Mayo Clinic
Naoki Takahashi: Mayo Clinic
Motokazu Sugimoto: Mayo Clinic
Jen Jen Yeh: University of North Carolina at Chapel Hill
Nicole Lopez: University of California San Diego School of Medicine
Nabeel Bardeesy: Harvard Medical School
Carlos Fernandez-del Castillo: Harvard Medical School
Andrew S. Liss: Harvard Medical School
Albert C. Koong: MD Anderson, Department of Radiation Oncology
Justin Bui: Stanford Cancer Institute
Chen Yuan: Dana-Farber Cancer Institute
Marisa W. Welch: Dana-Farber Cancer Institute
Lauren K. Brais: Dana-Farber Cancer Institute
Matthew H. Kulke: Dana-Farber Cancer Institute
Courtney Dennis: Broad Institute of MIT and Harvard University
Clary B. Clish: Broad Institute of MIT and Harvard University
Brian M. Wolpin: Dana-Farber Cancer Institute
Matthew G. Vander Heiden: Massachusetts Institute of Technology

Nature, 2018, vol. 558, issue 7711, 600-604

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0235-7

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