Dev Cell. 2026 May 19:S1534-5807(26)00159-0. doi: 10.1016/j.devcel.2026.04.012. Online ahead of print.

ABSTRACT

The lack of accurate human models that recapitulate pancreatic ductal adenocarcinoma (PDAC) initiation has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectories of tumor initiation and progression, validated against clinical datasets and tumor histopathology. We demonstrate that CDKN2A loss, which is nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, whereas SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of the pancreatic lineage program during PDAC initiation, alongside AP-1-driven chromatin remodeling. We identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and hypermethylation of essential pancreatic transcription factors. This model captures genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a potential early intervention strategy.

PMID:42161274 | PMC:PMC13196429 | DOI:10.1016/j.devcel.2026.04.012

bioRxiv [Preprint]. 2026 Mar 11:2026.03.09.710586. doi: 10.64898/2026.03.09.710586.

ABSTRACT

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

PMID:41959451 | PMC:PMC13060829 | DOI:10.64898/2026.03.09.710586