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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., Competing Interests: Competing interests: CRV has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics, has served on the scientific advisory board of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences, has received research funding from Boehringer-Ingelheim and Treeline Biosciences, and has received a stock option from Treeline Biosciences outside of the submitted work. DAT is a member of the Scientific Advisory Board and receives stock options from Leap Therapeutics, Surface Oncology, and Cygnal Therapeutics and Mestag Therapeutics outside the submitted work. DAT is scientific cofounder of Mestag Therapeutics. DAT has received research grant support from Fibrogen, Mestag and ONO Therapeutics. DAT receives grant funding from the Lustgarten Foundation, the NIH and the Thompson Foundation., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)