Resolution of Acinar Dedifferentiation Regulates Tissue Remodeling in Pancreatic Injury and Cancer Initiation
Year: 2024
Type: article
Abstract: BACKGROUND & AIMS: Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human. METHODS: ). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization, and single-cell RNA sequencing. RESULTS: We demonstrated that Sox4 is reactivated in ADM and pancreatic intraepithelial neoplasias. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression. CONCLUSIONS: Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of pancreatic ductal adenocarcinoma.
Source: Gastroenterology
Authors: Jonathan Baldan, Juan Camacho-Roda, Marta Ballester, Kristina Høj, Anita Kurilla, H. Carlo Maurer, Sebastian Arcila-Barrera, Xinyi Lin, Zhaolong Pan, Joana Leitão Castro, Alejandro Enrique Mayorca-Guiliani, Charlotte Vestrup Rift, Jane Hasselby, Luc Bouwens, Véronique Lefebvre, Charles J. David, Oren Parnas, Kathleen E. DelGiorno, Janine Terra Erler, Ilse Rooman, Luis Arnes
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,180
Funders: U.S. Department of Defense, Vanderbilt-Ingram Cancer Center, Kræftens Bekæmpelse, American Gastroenterological Association, Fonds Wetenschappelijk Onderzoek, Novo Nordisk Fonden, National Institutes of Health, Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, Horizon 2020, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, H2020 Marie Skłodowska-Curie Actions
Awards: G1450627757, G155838707, G1777002798, G1834197733, TARGETING MUTATIONAL DRIVERS IN IPMN USING LIPID NANOPARTICLE DELIVERY SYSTEMS, G3323367120, G3382714791, G3589578894, G5287830130, G6318372567, De-convolution of tumour biology in the post-genomic era: focus on pancreatic cancer, Postdoc to research LEADer programme, G6912796986, G725763919, G7339845255, Acinar cell specific susceptibility for tumor development in the pancreas: target the critical regulators for therapy, G7856352684, G801066051
OpenAlex ID: W4396776903