Tonelli, Claudia, Yordanov, Georgi N, Hao, Yuan, Deschênes, Astrid, Hinds, Juliene, Belleau, Pascal, Klingbeil, Olaf, Brosnan, Erin, Doshi, Abhishek, Park, Youngkyu, Hruban, Ralph H, Vakoc, Christopher R, Dobin, Alexander, Preall, Jonathan, Tuveson, David A (January 2024) A mucus production programme promotes classical pancreatic ductal adenocarcinoma. Gut. ISSN 0017-5749
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Abstract
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 towards basal-like differentiation. CONCLUSIONS: 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Microscopy Service CSHL Cancer Center Shared Resources > Single-Cell Biology Service CSHL labs > Hammell M. lab CSHL labs > Krasnitz lab CSHL labs > Preall lab CSHL labs > Tuveson lab CSHL labs > Vakoc lab CSHL labs > Dobin Lab School of Biological Sciences > Publications |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 23 January 2024 |
| Date Deposited: | 25 Jan 2024 13:56 |
| Last Modified: | 02 Jul 2024 19:49 |
| PMCID: | PMC11088527 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41420 |
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