A mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of pancreatic ductal adenocarcinoma (PDA). SPDEF maintains classical differentiation and supports PDA transformation in vivo. The SPDEF tumour-promoting function 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 towards basal-like differentiation. The findings expand understanding of transcriptional programmes in precancerous lesions and classical PDA, identify mucus production as a specific vulnerability, and reveal phenotype switching as a response to inactivation of differentiation state determinants. The SPDEF-regulated enzymes AGR2 and ERN2/IREβ represent new therapeutic targets for classical PDA. Comprehensive investigation of cell state interconversions during treatment may avoid relapse and improve overall responses in PDA patients. Combination strategies that suppress distinct cell states may be required to overcome resistance. The SPDEF programme is expressed in human precancerous lesions and classical PDAs. SPDEF is highly expressed in classical PDAs and absent or only weakly expressed in basal-like PDAs. SPDEF supports the growth of classical PDA and prevents aberrant mucus production. Inactivation of SPDEF leads to a classical-to-basal-like phenotype switch. SPDEF and its target genes ERN2/IRE1β and AGR2 support the fitness of classical PDAs. In response to their abrogation, tumours initiate a classical-to-basal-like phenotype switch. The study reveals that SPDEF is a mediator of epithelial/classical identity and its activity is dependent on the cell differentiation state. SPDEF loss facilitates subtype interconversion from classical towards basal-like differentiation. Mucin production plays an important role in the biology of normal and diseased pancreas. SPDEF is one but not the only regulator of mucus production in PDA. Mucus-secreting cells must adapt the activity of their ER to sustain the complex folding and glycosylation of secreted proteins. One of the strategies adopted by mucus-producing PDAs to deal with the stress caused by mucus production is to activate the ER stress response.A mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of pancreatic ductal adenocarcinoma (PDA). SPDEF maintains classical differentiation and supports PDA transformation in vivo. The SPDEF tumour-promoting function 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 towards basal-like differentiation. The findings expand understanding of transcriptional programmes in precancerous lesions and classical PDA, identify mucus production as a specific vulnerability, and reveal phenotype switching as a response to inactivation of differentiation state determinants. The SPDEF-regulated enzymes AGR2 and ERN2/IREβ represent new therapeutic targets for classical PDA. Comprehensive investigation of cell state interconversions during treatment may avoid relapse and improve overall responses in PDA patients. Combination strategies that suppress distinct cell states may be required to overcome resistance. The SPDEF programme is expressed in human precancerous lesions and classical PDAs. SPDEF is highly expressed in classical PDAs and absent or only weakly expressed in basal-like PDAs. SPDEF supports the growth of classical PDA and prevents aberrant mucus production. Inactivation of SPDEF leads to a classical-to-basal-like phenotype switch. SPDEF and its target genes ERN2/IRE1β and AGR2 support the fitness of classical PDAs. In response to their abrogation, tumours initiate a classical-to-basal-like phenotype switch. The study reveals that SPDEF is a mediator of epithelial/classical identity and its activity is dependent on the cell differentiation state. SPDEF loss facilitates subtype interconversion from classical towards basal-like differentiation. Mucin production plays an important role in the biology of normal and diseased pancreas. SPDEF is one but not the only regulator of mucus production in PDA. Mucus-secreting cells must adapt the activity of their ER to sustain the complex folding and glycosylation of secreted proteins. One of the strategies adopted by mucus-producing PDAs to deal with the stress caused by mucus production is to activate the ER stress response.