Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma

被引：105

作者：

Chung, Katherine Minjee ^{[1
]}

Singh, Jaffarguriqbal ^{[2
,3
]}

Lawres, Lauren ^{[2
,3
]}

Dorans, Kimberly Judith ^{[1
]}

Garcia, Cathy ^{[2
,3
]}

Burkhardt, Daniel B. ^{[2
]}

Robbins, Rebecca ^{[1
]}

Bhutkar, Arjun ^{[1
]}

Cardone, Rebecca ^{[4
,5
]}

Zhao, Xiaojian ^{[4
,5
]}

Babic, Ana ^{[6
]}

Vayrynen, Sara A. ^{[6
]}

Costa, Andressa Dias ^{[6
]}

Nowak, Jonathan A. ^{[7
]}

Chang, Daniel T. ^{[8
]}

Dunne, Richard F. ^{[9
]}

Hezel, Aram F. ^{[9
]}

Koong, Albert C. ^{[10
]}

Wilhelm, Joshua J. ^{[11
,12
]}

Bellin, Melena D. ^{[11
,12
,13
]}

Nylander, Vibe ^{[14
]}

Gloyn, Anna L. ^{[14
,15
,16
,20
]}

McCarthy, Mark, I ^{[14
,15
,16
,19
]}

Kibbey, Richard G. ^{[4
,5
]}

Krishnaswamy, Smita ^{[2
]}

Wolpin, Brian M. ^{[6
]}

Jacks, Tyler ^{[1
,17
]}

Fuchs, Charles S. ^{[18
]}

Muzumdar, Mandar Deepak ^{[2
,3
,18
]}

机构：

[1] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[3] Yale Univ, Yale Canc Biol Inst, West Haven, CT 06516 USA

[4] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA

[5] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA

[6] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02114 USA

[7] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[8] Stanford Canc Inst, Dept Radiat Oncol, Stanford, CA 94305 USA

[9] Univ Rochester, Med Ctr, Wilmot Canc Inst, Dept Med,Div Hematol & Oncol, Rochester, NY 14627 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[11] Univ Minnesota, Med Ctr, Schulze Diabet Inst, Minneapolis, MN 55454 USA

[12] Univ Minnesota, Med Ctr, Dept Surg, Minneapolis, MN 55454 USA

[13] Univ Minnesota, Med Ctr, Dept Pediat, Minneapolis, MN 55454 USA

[14] Univ Oxford, Wellcome Ctr Human Genet, Nuffield Dept Med, Oxford OX3 7BN, England

[15] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford OX3 7LE, England

[16] Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LE, England

[17] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[18] Smilow Canc Hosp, Yale Canc Ctr, New Haven, CT 06511 USA

[19] Genentech Inc, 340 Point San Bruno Blvd, San Francisco, CA 94080 USA

[20] Stanford Sch Med, Dept Pediat, Stanford, CA 94305 USA

来源：

CELL | 2020年 / 181卷 / 04期

基金：

英国医学研究理事会; 欧盟地平线“2020”; 英国惠康基金;

关键词：

BODY-MASS INDEX; CANCER RISK; INSULIN-SECRETION; ONCOGENIC KRAS; CELL-CYCLE; CHOLECYSTOKININ; PROGRESSION; RECEPTOR; RESISTANCE; MODELS;

D O I：

10.1016/j.cell.2020.03.062

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.

引用

页码：832 / +

页数：34

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