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

The transition from benign to malignant growth is a pivotal yet poorly understood step in cancer progression that marks the shift from a pathologically inert condition to a clinically lethal disease. 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. Conversely, p53 suppression enables progenitor cell expansion, epithelial–mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state as the convergence point of cancer-driving mutations, plasticity, and tissue remodeling—revealing a critical window for intercepting malignancy at its origin.