Abstract
Abstract The detailed understanding of the molecular basis of tumor initiation and progression is essential for the effective management and treatment of any cancer, including pancreatic cancer. To determine if the stem and progenitor cells can serve as cells of origin for pancreatic cancer, we have created a new mouse strain in which tamoxifen inducible Cre (CreERT2) is knocked into the endogenous locus encoding the stem cell regulator Musashi2 (Msi2). When crossed to a Cre-regulatable Myc transgenic (CAG-LSL-MycT58A) strain, Msi2-CreERT2 mice develop multiple pancreatic cancer subtypes: pancreatic ductal adenocarcinoma (PDAC), adenosquamous carcinoma of the pancreas (ASCP), and acinar cell carcinoma (ACC) following Myc activation in Msi2+ cells in the adult stage. A combination of single-cell genomics with computational analysis of developmental states and lineage trajectories of tumors in our model suggests that oncogenic Myc preferentially triggers the transformation of the most immature subset of Msi2+ cells, leading to the rise of a common pool of pre-cancer cells with multi-lineage potential. These pre-cancer cells subsequently take distinct fates within the same mice by activation of distinct transcriptional programs and large-scale genomic changes. Additionally, combining transcriptomic and functional genomic approaches, we have identified hyaluronan-mediated motility receptor (HMMR) as a potential novel dependency in mouse and human ASCP cells, providing a framework to develop interception strategies for this lethal disease. In summary, our study shows that multiple pancreatic cancer subtypes can arise from a common pool of Msi2+ cells and provides a powerful framework to understand and control the programs that shape divergent fates in pancreatic cancer. Citation Format: Nirakar Rajbhandari, Michael Hamilton, Tannishtha Reya. Single-cell mapping reveals a common origin for diverse subtypes of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR13.
Published Version
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