ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis
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.
Authors
- Jennifer P. Morton (ORCID: https://orcid.org/0000-0001-5766-9141)
- Morwenna Muir (ORCID: https://orcid.org/0000-0001-5835-3886)
- Damian J. Mole (ORCID: https://orcid.org/0000-0001-6884-7302)
- Alain J. Kemp
- Alex von Kriegsheim (ORCID: https://orcid.org/0000-0002-4952-8573)
- Simon Wilkinson
- Carla Salomó Coll
- Roopesh Krishnankutty (ORCID: https://orcid.org/0000-0002-1496-6135)
- Marisa Di Monaco
- Hywel Dunn-Davies (ORCID: https://orcid.org/0000-0003-3975-788X)
- Philippe Emmanuel Gautier (ORCID: https://orcid.org/0000-0003-3019-6262)
- Matthew D. Smith (ORCID: https://orcid.org/0000-0001-7603-8628)
- Natalia Jiménez-Moreno (ORCID: https://orcid.org/0000-0002-3934-7015)
- Xiaozhong Zheng (ORCID: https://orcid.org/0000-0002-9803-9688)
- Katie Winnington-Ingram
- Jocelyn Holkham
Institutions
- Edinburgh Cancer Research (GB)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- Centre for Inflammation Research (GB)
- Institute of Genetics and Cancer (GB)
- University of Glasgow (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Developmental Cell
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1016/j.devcel.2025.07.016
- Citations
- 3
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Beatson Institute for Cancer Research