ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis

Carla Salomó Coll; Marisa Di Monaco; Jocelyn Holkham; Matthew Smith; Morwenna Muir; Philippe Gautier; Hywel Dunn-Davies; Xiaozhong Zheng; Roopesh Krishnankutty; Alain J. Kemp; Katie Winnington-Ingram; Alex von Kriegsheim; Jennifer P. Morton; Natalia Jimenez-Moreno; Damian Mole; Simon Wilkinson

doi:10.1016/j.devcel.2025.07.016

ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis

Carla Salomó Coll
, Marisa Di Monaco
, Jocelyn Holkham
, Matthew Smith
, Morwenna Muir
, Philippe Gautier
, Hywel Dunn-Davies
, Xiaozhong Zheng
, Roopesh Krishnankutty
, Alain J. Kemp
, Katie Winnington-Ingram
, Alex von Kriegsheim
, Jennifer P. Morton
, Natalia Jimenez-Moreno
, Damian Mole
, Simon Wilkinson (Lead / Corresponding author)

MRC PPU

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

4 Citations (Scopus)

Abstract

Pre-malignant transformation of pancreatic acinar cells by oncogenic Kras is dependent upon stochastic emergence of metaplastic cell states. Here, we reveal that an early, transcriptionally mediated effect of Kras is sporadic failure of proteostatic endoplasmic reticulum (ER)-phagy. Genetically altered mice deficient in ER-phagy demonstrate that this event cooperates with Kras to drive acinar-ductal metaplasia (ADM) and subsequent cancer. Mechanistically, proteomics and high-resolution imaging uncover pathologic aggregation of a subset of ER proteins, including the injury marker REG3B, resulting from failure to physically interact with the ER-phagy receptor CCPG1. Spatial transcriptomics demonstrate that the appearance of sporadic intracellular aggregates upon Kras activation marks rare acinar cells existing in an injured, ADM-primed state. Importantly, engineered mutants of REG3B establish that aggregate formation is sufficient to directly engender this epithelial cell state. Pancreatic cancer can thus arise from stochastic pathologic protein aggregates that are influenced by, and cooperate with, an oncogene.

Original language	English
Journal	Developmental Cell
Volume	60
Early online date	14 Aug 2025
DOIs	https://doi.org/10.1016/j.devcel.2025.07.016
Publication status	E-pub ahead of print - 14 Aug 2025

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

ADM
autophagy
CANCER
CCPG1
ER-phagy
inflammation
KRAS
metaplasia
pancreas
proteostasis

ASJC Scopus subject areas

Molecular Biology
General Biochemistry,Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2025.07.016Licence: CC BY

Cite this

Salomó Coll, C., Di Monaco, M., Holkham, J., Smith, M., Muir, M., Gautier, P., Dunn-Davies, H., Zheng, X., Krishnankutty, R., Kemp, A. J., Winnington-Ingram, K., von Kriegsheim, A., Morton, J. P., Jimenez-Moreno, N., Mole, D., & Wilkinson, S. (2025). ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis. Developmental Cell, 60. Advance online publication. https://doi.org/10.1016/j.devcel.2025.07.016

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title = "ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis",

abstract = "Pre-malignant transformation of pancreatic acinar cells by oncogenic Kras is dependent upon stochastic emergence of metaplastic cell states. Here, we reveal that an early, transcriptionally mediated effect of Kras is sporadic failure of proteostatic endoplasmic reticulum (ER)-phagy. Genetically altered mice deficient in ER-phagy demonstrate that this event cooperates with Kras to drive acinar-ductal metaplasia (ADM) and subsequent cancer. Mechanistically, proteomics and high-resolution imaging uncover pathologic aggregation of a subset of ER proteins, including the injury marker REG3B, resulting from failure to physically interact with the ER-phagy receptor CCPG1. Spatial transcriptomics demonstrate that the appearance of sporadic intracellular aggregates upon Kras activation marks rare acinar cells existing in an injured, ADM-primed state. Importantly, engineered mutants of REG3B establish that aggregate formation is sufficient to directly engender this epithelial cell state. Pancreatic cancer can thus arise from stochastic pathologic protein aggregates that are influenced by, and cooperate with, an oncogene.",

keywords = "ADM, autophagy, CANCER, CCPG1, ER-phagy, inflammation, KRAS, metaplasia, pancreas, proteostasis",

author = "\{Salom{\'o} Coll\}, Carla and \{Di Monaco\}, Marisa and Jocelyn Holkham and Matthew Smith and Morwenna Muir and Philippe Gautier and Hywel Dunn-Davies and Xiaozhong Zheng and Roopesh Krishnankutty and Kemp, \{Alain J.\} and Katie Winnington-Ingram and \{von Kriegsheim\}, Alex and Morton, \{Jennifer P.\} and Natalia Jimenez-Moreno and Damian Mole and Simon Wilkinson",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = aug,

day = "14",

doi = "10.1016/j.devcel.2025.07.016",

language = "English",

volume = "60",

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Salomó Coll, C, Di Monaco, M, Holkham, J, Smith, M, Muir, M, Gautier, P, Dunn-Davies, H, Zheng, X, Krishnankutty, R, Kemp, AJ, Winnington-Ingram, K, von Kriegsheim, A, Morton, JP, Jimenez-Moreno, N, Mole, D & Wilkinson, S 2025, 'ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis', Developmental Cell, vol. 60. https://doi.org/10.1016/j.devcel.2025.07.016

TY - JOUR

T1 - ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis

AU - Salomó Coll, Carla

AU - Di Monaco, Marisa

AU - Holkham, Jocelyn

AU - Smith, Matthew

AU - Muir, Morwenna

AU - Gautier, Philippe

AU - Dunn-Davies, Hywel

AU - Zheng, Xiaozhong

AU - Krishnankutty, Roopesh

AU - Kemp, Alain J.

AU - Winnington-Ingram, Katie

AU - von Kriegsheim, Alex

AU - Morton, Jennifer P.

AU - Jimenez-Moreno, Natalia

AU - Mole, Damian

AU - Wilkinson, Simon

PY - 2025/8/14

Y1 - 2025/8/14

N2 - Pre-malignant transformation of pancreatic acinar cells by oncogenic Kras is dependent upon stochastic emergence of metaplastic cell states. Here, we reveal that an early, transcriptionally mediated effect of Kras is sporadic failure of proteostatic endoplasmic reticulum (ER)-phagy. Genetically altered mice deficient in ER-phagy demonstrate that this event cooperates with Kras to drive acinar-ductal metaplasia (ADM) and subsequent cancer. Mechanistically, proteomics and high-resolution imaging uncover pathologic aggregation of a subset of ER proteins, including the injury marker REG3B, resulting from failure to physically interact with the ER-phagy receptor CCPG1. Spatial transcriptomics demonstrate that the appearance of sporadic intracellular aggregates upon Kras activation marks rare acinar cells existing in an injured, ADM-primed state. Importantly, engineered mutants of REG3B establish that aggregate formation is sufficient to directly engender this epithelial cell state. Pancreatic cancer can thus arise from stochastic pathologic protein aggregates that are influenced by, and cooperate with, an oncogene.

AB - Pre-malignant transformation of pancreatic acinar cells by oncogenic Kras is dependent upon stochastic emergence of metaplastic cell states. Here, we reveal that an early, transcriptionally mediated effect of Kras is sporadic failure of proteostatic endoplasmic reticulum (ER)-phagy. Genetically altered mice deficient in ER-phagy demonstrate that this event cooperates with Kras to drive acinar-ductal metaplasia (ADM) and subsequent cancer. Mechanistically, proteomics and high-resolution imaging uncover pathologic aggregation of a subset of ER proteins, including the injury marker REG3B, resulting from failure to physically interact with the ER-phagy receptor CCPG1. Spatial transcriptomics demonstrate that the appearance of sporadic intracellular aggregates upon Kras activation marks rare acinar cells existing in an injured, ADM-primed state. Importantly, engineered mutants of REG3B establish that aggregate formation is sufficient to directly engender this epithelial cell state. Pancreatic cancer can thus arise from stochastic pathologic protein aggregates that are influenced by, and cooperate with, an oncogene.

KW - ADM

KW - autophagy

KW - CANCER

KW - CCPG1

KW - ER-phagy

KW - inflammation

KW - KRAS

KW - metaplasia

KW - pancreas

KW - proteostasis

UR - https://www.scopus.com/pages/publications/105013175138

U2 - 10.1016/j.devcel.2025.07.016

DO - 10.1016/j.devcel.2025.07.016

M3 - Article

C2 - 40816286

AN - SCOPUS:105013175138

SN - 1534-5807

VL - 60

JO - Developmental Cell

JF - Developmental Cell

ER -

ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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