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 M Takahashi, Motokazu Sugimoto, Jen Jen Yeh, Nicole Lopez, Nabeel Bardeesy, Carlos Fernandez-Del Castillo, Andrew S. Liss, Albert C. KoongJustin Bui, Chen Yuan, Marisa W. Welch, Lauren K. Brais, Matthew H. Kulke, Courtney Dennis, Clary B. Clish, Brian M. Wolpin, Matthew G. Vander Heiden

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Malignancy is accompanied by changes in the metabolism of both cells and the organism 1,2 . 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 cancer 3,4 . Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic 5,6 . 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.

Original languageEnglish (US)
Pages (from-to)600-604
Number of pages5
JournalNature
Volume558
Issue number7711
DOIs
StatePublished - Jun 28 2018

Fingerprint

Pancreatic Neoplasms
Adenocarcinoma
Adipose Tissue
Survival
Neoplasms
Muscles
Growth
Pancreas
Skeletal Muscle
Quality of Life
Phenotype
Enzymes

ASJC Scopus subject areas

  • General

Cite this

Danai, L. V., Babic, A., Rosenthal, M. H., Dennstedt, E. A., Muir, A., Lien, E. C., ... Vander Heiden, M. G. (2018). Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature, 558(7711), 600-604. https://doi.org/10.1038/s41586-018-0235-7

Altered exocrine function can drive adipose wasting in early pancreatic cancer. / Danai, Laura V.; Babic, Ana; Rosenthal, Michael H.; Dennstedt, Emily A.; Muir, Alexander; Lien, Evan C.; Mayers, Jared R.; Tai, Karen; Lau, Allison N.; Jones-Sali, Paul; Prado, Carla M.; Petersen, Gloria M; Takahashi, Naoki M; Sugimoto, Motokazu; Yeh, Jen Jen; Lopez, Nicole; Bardeesy, Nabeel; Fernandez-Del Castillo, Carlos; Liss, Andrew S.; Koong, Albert C.; Bui, Justin; Yuan, Chen; Welch, Marisa W.; Brais, Lauren K.; Kulke, Matthew H.; Dennis, Courtney; Clish, Clary B.; Wolpin, Brian M.; Vander Heiden, Matthew G.

In: Nature, Vol. 558, No. 7711, 28.06.2018, p. 600-604.

Research output: Contribution to journalArticle

Danai, LV, Babic, A, Rosenthal, MH, Dennstedt, EA, Muir, A, Lien, EC, Mayers, JR, Tai, K, Lau, AN, Jones-Sali, P, Prado, CM, Petersen, GM, Takahashi, NM, Sugimoto, M, Yeh, JJ, Lopez, N, Bardeesy, N, Fernandez-Del Castillo, C, Liss, AS, Koong, AC, Bui, J, Yuan, C, Welch, MW, Brais, LK, Kulke, MH, Dennis, C, Clish, CB, Wolpin, BM & Vander Heiden, MG 2018, 'Altered exocrine function can drive adipose wasting in early pancreatic cancer', Nature, vol. 558, no. 7711, pp. 600-604. https://doi.org/10.1038/s41586-018-0235-7
Danai LV, Babic A, Rosenthal MH, Dennstedt EA, Muir A, Lien EC et al. Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature. 2018 Jun 28;558(7711):600-604. https://doi.org/10.1038/s41586-018-0235-7
Danai, Laura V. ; Babic, Ana ; Rosenthal, Michael H. ; Dennstedt, Emily A. ; Muir, Alexander ; Lien, Evan C. ; Mayers, Jared R. ; Tai, Karen ; Lau, Allison N. ; Jones-Sali, Paul ; Prado, Carla M. ; Petersen, Gloria M ; Takahashi, Naoki M ; Sugimoto, Motokazu ; Yeh, Jen Jen ; Lopez, Nicole ; Bardeesy, Nabeel ; Fernandez-Del Castillo, Carlos ; Liss, Andrew S. ; Koong, Albert C. ; Bui, Justin ; Yuan, Chen ; Welch, Marisa W. ; Brais, Lauren K. ; Kulke, Matthew H. ; Dennis, Courtney ; Clish, Clary B. ; Wolpin, Brian M. ; Vander Heiden, Matthew G. / Altered exocrine function can drive adipose wasting in early pancreatic cancer. In: Nature. 2018 ; Vol. 558, No. 7711. pp. 600-604.
@article{c38cb8b8216c45a8a9b8b0dece70f54f,
title = "Altered exocrine function can drive adipose wasting in early pancreatic cancer",
abstract = "Malignancy is accompanied by changes in the metabolism of both cells and the organism 1,2 . 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 cancer 3,4 . Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic 5,6 . 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.",
author = "Danai, {Laura V.} and Ana Babic and Rosenthal, {Michael H.} and Dennstedt, {Emily A.} and Alexander Muir and Lien, {Evan C.} and Mayers, {Jared R.} and Karen Tai and Lau, {Allison N.} and Paul Jones-Sali and Prado, {Carla M.} and Petersen, {Gloria M} and Takahashi, {Naoki M} and Motokazu Sugimoto and Yeh, {Jen Jen} and Nicole Lopez and Nabeel Bardeesy and {Fernandez-Del Castillo}, Carlos and Liss, {Andrew S.} and Koong, {Albert C.} and Justin Bui and Chen Yuan and Welch, {Marisa W.} and Brais, {Lauren K.} and Kulke, {Matthew H.} and Courtney Dennis and Clish, {Clary B.} and Wolpin, {Brian M.} and {Vander Heiden}, {Matthew G.}",
year = "2018",
month = "6",
day = "28",
doi = "10.1038/s41586-018-0235-7",
language = "English (US)",
volume = "558",
pages = "600--604",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7711",

}

TY - JOUR

T1 - Altered exocrine function can drive adipose wasting in early pancreatic cancer

AU - Danai, Laura V.

AU - Babic, Ana

AU - Rosenthal, Michael H.

AU - Dennstedt, Emily A.

AU - Muir, Alexander

AU - Lien, Evan C.

AU - Mayers, Jared R.

AU - Tai, Karen

AU - Lau, Allison N.

AU - Jones-Sali, Paul

AU - Prado, Carla M.

AU - Petersen, Gloria M

AU - Takahashi, Naoki M

AU - Sugimoto, Motokazu

AU - Yeh, Jen Jen

AU - Lopez, Nicole

AU - Bardeesy, Nabeel

AU - Fernandez-Del Castillo, Carlos

AU - Liss, Andrew S.

AU - Koong, Albert C.

AU - Bui, Justin

AU - Yuan, Chen

AU - Welch, Marisa W.

AU - Brais, Lauren K.

AU - Kulke, Matthew H.

AU - Dennis, Courtney

AU - Clish, Clary B.

AU - Wolpin, Brian M.

AU - Vander Heiden, Matthew G.

PY - 2018/6/28

Y1 - 2018/6/28

N2 - Malignancy is accompanied by changes in the metabolism of both cells and the organism 1,2 . 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 cancer 3,4 . Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic 5,6 . 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.

AB - Malignancy is accompanied by changes in the metabolism of both cells and the organism 1,2 . 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 cancer 3,4 . Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic 5,6 . 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.

UR - http://www.scopus.com/inward/record.url?scp=85049254963&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049254963&partnerID=8YFLogxK

U2 - 10.1038/s41586-018-0235-7

DO - 10.1038/s41586-018-0235-7

M3 - Article

C2 - 29925948

AN - SCOPUS:85049254963

VL - 558

SP - 600

EP - 604

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7711

ER -