Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Jelena Todoric; Laura Antonucci; Giuseppe Di Caro; Ning Li; Xuefeng Wu; Nikki K. Lytle; Debanjan Dhar; Sourav Banerjee; Johan B. Fagman; Cecille D. Browne; Atsushi Umemura; Mark A. Valasek; Hannes Kessler; David Tarin; Michael Goggins; Tannishtha Reya; Maria Diaz-Meco; Jorge Moscat; Michael Karin

doi:10.1016/j.ccell.2017.10.011

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Jelena Todoric, Laura Antonucci, Giuseppe Di Caro, Ning Li, Xuefeng Wu, Nikki K. Lytle, Debanjan Dhar, Sourav Banerjee, Johan B. Fagman, Cecille D. Browne, Atsushi Umemura, Mark A. Valasek, Hannes Kessler, David Tarin, Michael Goggins, Tannishtha Reya, Maria Diaz-Meco, Jorge Moscat, Michael Karin

Research output: Contribution to journal › Article › peer-review

100 Citations (Scopus)

Abstract

Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed Kras^G12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals. Todoric et al. demonstrate that pancreatitis-induced accumulation of the autophagy substrate p62/SQSTM1 in the context of oncogenic KRAS promotes progression to pancreatic ductal adenocarcinoma. This p62 function relies on NRF2-driven induction of MDM2 and both p53 dependent and independent activity of MDM2.

Original language	English
Pages (from-to)	824-839.e8
Journal	Cancer Cell
Volume	32
Issue number	6
Early online date	16 Nov 2017
DOIs	https://doi.org/10.1016/j.ccell.2017.10.011
Publication status	Published - 11 Dec 2017

Keywords

acinar cell reprogramming
IKKα
impaired autophagy
MDM2
NRF2
p62
pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2017.10.011

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Todoric, J., Antonucci, L., Di Caro, G., Li, N., Wu, X., Lytle, N. K., Dhar, D., Banerjee, S., Fagman, J. B., Browne, C. D., Umemura, A., Valasek, M. A., Kessler, H., Tarin, D., Goggins, M., Reya, T., Diaz-Meco, M., Moscat, J., & Karin, M. (2017). Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. Cancer Cell, 32(6), 824-839.e8. https://doi.org/10.1016/j.ccell.2017.10.011

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title = "Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas",

abstract = "Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals. Todoric et al. demonstrate that pancreatitis-induced accumulation of the autophagy substrate p62/SQSTM1 in the context of oncogenic KRAS promotes progression to pancreatic ductal adenocarcinoma. This p62 function relies on NRF2-driven induction of MDM2 and both p53 dependent and independent activity of MDM2.",

keywords = "acinar cell reprogramming, IKKα, impaired autophagy, MDM2, NRF2, p62, pancreatic ductal adenocarcinoma",

author = "Jelena Todoric and Laura Antonucci and {Di Caro}, Giuseppe and Ning Li and Xuefeng Wu and Lytle, {Nikki K.} and Debanjan Dhar and Sourav Banerjee and Fagman, {Johan B.} and Browne, {Cecille D.} and Atsushi Umemura and Valasek, {Mark A.} and Hannes Kessler and David Tarin and Michael Goggins and Tannishtha Reya and Maria Diaz-Meco and Jorge Moscat and Michael Karin",

year = "2017",

month = dec,

day = "11",

doi = "10.1016/j.ccell.2017.10.011",

language = "English",

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pages = "824--839.e8",

journal = "Cancer Cell",

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Todoric, J, Antonucci, L, Di Caro, G, Li, N, Wu, X, Lytle, NK, Dhar, D, Banerjee, S, Fagman, JB, Browne, CD, Umemura, A, Valasek, MA, Kessler, H, Tarin, D, Goggins, M, Reya, T, Diaz-Meco, M, Moscat, J & Karin, M 2017, 'Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas', Cancer Cell, vol. 32, no. 6, pp. 824-839.e8. https://doi.org/10.1016/j.ccell.2017.10.011

TY - JOUR

T1 - Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

AU - Todoric, Jelena

AU - Antonucci, Laura

AU - Di Caro, Giuseppe

AU - Li, Ning

AU - Wu, Xuefeng

AU - Lytle, Nikki K.

AU - Dhar, Debanjan

AU - Banerjee, Sourav

AU - Fagman, Johan B.

AU - Browne, Cecille D.

AU - Umemura, Atsushi

AU - Valasek, Mark A.

AU - Kessler, Hannes

AU - Tarin, David

AU - Goggins, Michael

AU - Reya, Tannishtha

AU - Diaz-Meco, Maria

AU - Moscat, Jorge

AU - Karin, Michael

PY - 2017/12/11

Y1 - 2017/12/11

N2 - Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals. Todoric et al. demonstrate that pancreatitis-induced accumulation of the autophagy substrate p62/SQSTM1 in the context of oncogenic KRAS promotes progression to pancreatic ductal adenocarcinoma. This p62 function relies on NRF2-driven induction of MDM2 and both p53 dependent and independent activity of MDM2.

AB - Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals. Todoric et al. demonstrate that pancreatitis-induced accumulation of the autophagy substrate p62/SQSTM1 in the context of oncogenic KRAS promotes progression to pancreatic ductal adenocarcinoma. This p62 function relies on NRF2-driven induction of MDM2 and both p53 dependent and independent activity of MDM2.

KW - acinar cell reprogramming

KW - IKKα

KW - impaired autophagy

KW - MDM2

KW - NRF2

KW - p62

KW - pancreatic ductal adenocarcinoma

UR - http://www.scopus.com/inward/record.url?scp=85034422866&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2017.10.011

DO - 10.1016/j.ccell.2017.10.011

M3 - Article

C2 - 29153842

AN - SCOPUS:85034422866

SN - 1535-6108

VL - 32

SP - 824-839.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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