Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis [Xenium]

Here, we integrate lineage tracing, single-cell and spatial transcriptomics to visualize the molecular, cellular and tissue-level events that promote or restrain malignancy during the tumor initiation in mouse models of pancreatic ductal adenocarcinoma (PDAC).

We identify a discrete progenitor-like population of KRAS-mutant cells that co-activates oncogenic and tumor-suppressive programs—including p53, CDKN2A, and SMAD4—engaging senescence-like responses and remodeling their microenvironment, ultimately assembling a niche that mirrors invasive PDAC. Even brief KRAS inhibition in the epithelial compartment depletes progenitor-like cells and dismantles their niche, substantially delaying cancer initiation.