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

• Published in: Cancer cell 2023-11, Vol.41 (11), p.1989-2005.e9
• Main Authors: Rajbhandari, Nirakar, Hamilton, Michael, Quintero, Cynthia M., Ferguson, L. Paige, Fox, Raymond, Schürch, Christian M., Wang, Jun, Nakamura, Mari, Lytle, Nikki K., McDermott, Matthew, Diaz, Emily, Pettit, Hannah, Kritzik, Marcie, Han, Haiyong, Cridebring, Derek, Wen, Kwun Wah, Tsai, Susan, Goggins, Michael G., Lowy, Andrew M., Wechsler-Reya, Robert J., Von Hoff, Daniel D., Newman, Aaron M., Reya, Tannishtha
• Format: Article
• Language: English
• Subjects: acinar cell carcinoma; adenosquamous carcinoma; Animals; cancer; Carcinoma, Pancreatic Ductal - pathology; cell of origin stem cells; Mice; Musashi; Myc; pancreatic cancer; Pancreatic Neoplasms - pathology; single cell; tumor evolution
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2023.09.008

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.