Tracing tumor evolution and subtype specification in pancreatic cancer

Identifying the cells from which cancers arise, and the paths they take towards malignancy, is critical for understanding the molecular basis of tumor initiation and progression. To understand if stem and progenitor cells can serve as cells of origin for cancer, we created a model in which the CreERT2 recombinase was knocked into the endogenous locus of the stem cell determinant Msi2. When crossed to a conditional CAG-LSL-MycT58A model, Msi2-CreERT2 mice developed a diversity of tumors across tissues, including multiple pancreatic cancer subtypes: pancreatic ductal adenocarcinoma (PDAC), adenosquamous carcinoma of the pancreas (ASCP), acinar cell carcinoma (ACC), and rare anaplastic tumors. Using single cell analysis, we traced the temporal changes that occurred as normal Msi2+ cells evolved through a pre-cancerous stage to PDAC, ASCP or ACC. These results revealed that Msi2+ cells were present predominantly in pancreatic ducts and exhibited heterogeneous differentiation states in the normal pancreas. At initiation, Myc triggered oncogenic transformation in the most undifferentiated subset leading to the rise of pre-cancer cells with multi-lineage properties. Subsequently, these pre-cancer cells were driven along different fates by epigenetically activated transcriptional programs with genomic changes amplifying the progression into distinct pancreatic cancer subtypes. Finally, integrating transcriptomic and functional genomic approaches in this new model allowed us to define Ifne, Ifitm3, Atf3, Hmmr, and Raet1e as novel functional dependencies of ASCP, giving us unique insight into the most lethal of pancreatic malignancies. These data show that multiple pancreatic cancer subtypes can arise from a common pool of pre-malignant cells and provide a powerful molecular framework to understand the programs that shape divergent fates in pancreas cancer and develop approaches for early detection and interception.