Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-CreERT2 knock-in mouse. When crossed to CAG-LSL-MycT58A mice, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2+ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer. [Display omitted] •Development of Msi2-CreERT2 knock-in mouse to express MYC in stem/progenitor cells•MSI2+ cells are cells of origin for multiple cancers such as lung, brain, and pancreas•Msi2-Myc mice form diverse pancreatic cancer subtypes from a common tumor precursor•Mapping dependencies of adenosquamous tumors identifies HMMR as a potential target Rajbhandari et al. report the development of a Msi2-CreERT2 mouse model which shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful framework to understand the programs that shape divergent fates in pancreatic cancer.