/wp-content/uploads/2017/02/reya-lab-120x267.png 0 0 Mathew Chvasta /wp-content/uploads/2017/02/reya-lab-120x267.png Mathew Chvasta2023-10-05 19:40:532023-10-05 19:49:21Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer
Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer
Nirakar Rajbhandari, Michael Hamilton, Cynthia M. Quintero, L. Paige Ferguson, Raymond Fox, Christian M. Schürch, Jun Wang, Mari Nakamura, Nikki K. Lytle, Matthew McDermott, Emily Diaz, Hannah Pettit, Marcie Kritzik, Haiyong Han, Derek Cridebring, Kwun Wah Wen, Susan Tsai, Michael G. Goggins, Andrew M. Lowy, Robert J. Wechsler-Reya, Daniel D. Von Hoff, Aaron M. Newman, Tannishtha Reya
Cancer Cell. 5 October 2023. doi: 10.1016/j.ccell.2023.09.008. Online ahead of print. PDF |
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.