Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis

被引：150

作者：

Del Poggetto, Edoardo ^{[1
,16
]}

Ho, I-Lin ^{[1
,2
]}

Balestrieri, Chiara ^{[3
,4
]}

Yen, Er-Yen ^{[1
,2
]}

Zhang, Shaojun ^{[1
,17
]}

Citron, Francesca ^{[1
]}

Shah, Rutvi ^{[1
,2
]}

Corti, Denise ^{[1
,18
]}

Diaferia, Giuseppe R. ^{[5
]}

Li, Chieh-Yuan ^{[1
,2
,19
]}

Loponte, Sara ^{[1
]}

Carbone, Federica ^{[1
,20
]}

Hayakawa, Yoku ^{[6
]}

Valenti, Giovanni ^{[6
]}

Jiang, Shan ^{[1
]}

Sapio, Luigi ^{[1
,21
]}

Jiang, Hong ^{[1
]}

Dey, Prasenjit ^{[7
,22
]}

Gao, Sisi ^{[1
]}

Deem, Angela K. ^{[1
]}

Rose-John, Stefan ^{[8
]}

Yao, Wantong ^{[9
]}

Ying, Haoqiang ^{[10
]}

Rhim, Andrew D. ^{[11
]}

Genovese, Giannicola ^{[12
]}

Heffernan, Timothy P. ^{[13
]}

Maitra, Anirban ^{[14
]}

Wang, Timothy C. ^{[6
]}

Wang, Linghua ^{[1
]}

Draetta, Giulio F. ^{[1
]}

Carugo, Alessandro ^{[13
]}

Natoli, Gioacchino ^{[5
,15
]}

Viale, Andrea ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[2] MD Anderson UTHlth Grad Sch Biomed Sci, Houston, TX 77030 USA

[3] San Raffaele Res Hosp, Expt Hematol Unit, I-20132 Milan, Italy

[4] IRCCS San Raffaele Sci Inst, Ctr Omics Sci, I-20132 Milan, Italy

[5] European Inst Oncol IRCCS, Dept Expt Oncol, I-20139 Milan, Italy

[6] Columbia Univ, Dept Digest & Liver Dis, Med Ctr, New York, NY 10032 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[8] Christian Albrechts Univ Kiel, Dept Biochem, D-24098 Kiel, Germany

[9] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

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

[11] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA

[13] Univ Texas MD Anderson Canc Ctr, TRACTION, Houston, TX 77030 USA

[14] Univ Texas MD Anderson Canc Ctr, Sheikh Ahmed Ctr Pancreat Canc Res, Houston, TX 77030 USA

[15] Humanitas Univ, I-20089 Milan, Italy

[16] AXXAM, I-20091 Milan, Italy

[17] Guangdong Acad Med Sci, Med Res Ctr, Guangdong Prov Peoples Hosp, Guangzhou 510080, Peoples R China

[18] F Hoffrrann La Roche Ltd, CH-4070 Basel, Switzerland

[19] Mission Bio, San Francisco, CA 94080 USA

[20] Nerviano Med Sci, I-20014 Nervier, Italy

[21] Univ Campania Luigi Vanvitelli, Dept Precis Med, I-80138 Naples, Italy

[22] Roswell Pk Comprehens Canc Ctr, Dept Immunol, Buffalo, NY 14263 USA

来源：

SCIENCE | 2021年 / 373卷 / 6561期

基金：

欧盟地平线“2020”;

关键词：

TO-DUCTAL METAPLASIA; DIFFERENTIAL EXPRESSION ANALYSIS; NF-KAPPA-B; ONCOGENIC KRAS; STEM-CELLS; INTRAEPITHELIAL NEOPLASIA; ACINAR; CANCER; ACTIVATION; GROWTH;

D O I：

10.1126/science.abj0486

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.

引用

页码：1326 / +

页数：45

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