A mucus production programme promotes classical pancreatic ductal adenocarcinoma

作者：Claudia Tonelli, Georgi N. Yordanov, Yuan Hao, Astrid Deschênes, Juliene Hinds, Pascal Belleau, Olaf Klingbeil, Erin Brosnan, Abhishek Doshi, Youngkyu Park, Ralph H. Hruban, Christopher R. Vakoc, Alexander Dobin, Jonathan Preall, David A. Tuveson · 发表于：Gut · 年份：2024 · DOI：10.1136/gutjnl-2023-329839 · 被引用次数：34 · 研究领域：Pancreatic and Hepatic Oncology Research、Cancer Cells and Metastasis、Single-cell and spatial transcriptomics

Objective The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators. Design We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models. Results Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA — the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation in vivo . The SPDEF tumour-promoting function is mediated by its target genes AGR2 and ERN2 /IRE1β that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical tow...