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-Cre ^ERT2 knock-in mouse. When crossed to CAG-LSL-Myc ^T58A mice, Msi2-Cre ^ERT2 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.
Competing Interests: Declaration of interests T.R. is a founder and member of the Board of Directors, and holds executive roles at Tiger Hill Therapeutics.
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