{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Tonelli C"],"funding":["Cold Spring Harbor Laboratory","Simons Foundation","Northwell Health","National Cancer Institute","Lustgarten Foundation","NCI NIH HHS","Pershing Square Foundation","National Institutes of Health","Thompson Foundation","American-Italian Cancer Foundation","NIH HHS"],"pagination":["941-954"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11088527"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["73(6)"],"pubmed_abstract":["<h4>Objective</h4>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.<h4>Design</h4>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.<h4>Results</h4>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 <i>in vivo</i>. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and <i>ERN2</i>/IRE1β that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation.<h4>Conclusions</h4>Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants."],"journal":["Gut"],"pubmed_title":["A mucus production programme promotes classical pancreatic ductal adenocarcinoma."],"pmcid":["PMC11088527"],"funding_grant_id":["R50 CA211506","P01 CA013106","R01 CA190092","U01CA224013","U01 CA224013","5P30CA45508","S10OD028632-01","1R01CA188134","NA","P30 CA045508","552716","R01 CA188134","1R01CA190092","S10 OD028632","U01 CA210240","U01CA210240","R01 CA229699","R50CA211506","R01CA229699"],"pubmed_authors":["Belleau P","Deschenes A","Yordanov GN","Hao Y","Hinds J","Preall J","Hruban RH","Tuveson DA","Park Y","Dobin A","Tonelli C","Klingbeil O","Vakoc CR","Brosnan E","Doshi A"],"additional_accession":[]},"is_claimable":false,"name":"A mucus production programme promotes classical pancreatic ductal adenocarcinoma.","description":"<h4>Objective</h4>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.<h4>Design</h4>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.<h4>Results</h4>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 <i>in vivo</i>. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and <i>ERN2</i>/IRE1β that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation.<h4>Conclusions</h4>Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 May","modification":"2026-06-09T07:11:46.197Z","creation":"2026-06-09T03:12:09.902Z"},"accession":"S-EPMC11088527","cross_references":{"pubmed":["38262672"],"doi":["10.1136/gutjnl-2023-329839"]}}