This study investigates the intratumour heterogeneity and plasticity of cancer cell states in pancreatic ductal adenocarcinoma (PDA) to identify cell state-specific regulators. Single-cell expression profiling of mouse PDAs revealed a mucus production programme regulated by the transcription factor SPDEF, which is highly active in precancerous lesions and classical PDA. SPDEF maintains the classical differentiation and supports PDA transformation in vivo. The tumour-promoting function of SPDEF is mediated by its target genes AGR2 and ERN2/IRE1β, which regulate mucus production. Inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical to basal-like differentiation. The findings expand our understanding of the transcriptional programmes active in precancerous lesions and classical PDAs, determine the regulators of mucus production as specific vulnerabilities, and reveal phenotype switching as a response mechanism to inactivation of differentiation state determinants.This study investigates the intratumour heterogeneity and plasticity of cancer cell states in pancreatic ductal adenocarcinoma (PDA) to identify cell state-specific regulators. Single-cell expression profiling of mouse PDAs revealed a mucus production programme regulated by the transcription factor SPDEF, which is highly active in precancerous lesions and classical PDA. SPDEF maintains the classical differentiation and supports PDA transformation in vivo. The tumour-promoting function of SPDEF is mediated by its target genes AGR2 and ERN2/IRE1β, which regulate mucus production. Inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical to basal-like differentiation. The findings expand our understanding of the transcriptional programmes active in precancerous lesions and classical PDAs, determine the regulators of mucus production as specific vulnerabilities, and reveal phenotype switching as a response mechanism to inactivation of differentiation state determinants.