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

Cancer Cell. 2023 Nov 13;41(11):1989-2005.e9. doi: 10.1016/j.ccell.2023.09.008. Epub 2023 Oct 5.


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.

Keywords: Musashi; Myc; acinar cell carcinoma; adenosquamous carcinoma; cancer; cell of origin stem cells; pancreatic cancer; single cell; tumor evolution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal* / pathology
  • Mice
  • Pancreatic Neoplasms* / pathology