Abstract
Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.
Highlights
Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer
To explore cell heterogeneity following the expression of constitutively active Kras in acinar cells, which causes acinar metaplasia and pancreatic dysplasia, we carried out scRNA-seq experiments of pancreatic tissues
Tamoxifen was injected into six- to eight-week-old Ptf1aCreER, LSL-Kras-G12D, LSL-tdTomato (PRT) mice, and the pancreas was collected for single-cell isolation at six different time points post-tamoxifen injection (PTI) (Fig. 1a–h)
Summary
Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Immune cells can be detected in pancreatic lesions and pancreatic tumors, but so far immunotherapy has not been shown to benefit PDAC patients[16], in part because of the dominant effect of suppressive cells in the tumor microenvironment (TME) Consistent with this possibility, depletion of myeloid cells, for example macrophages, reduces lesion formation and tumor volume in mice[17,18]. It is not known at which stage during the development of the disease the immunosuppressive environment is formed and what signals and cells are involved. We describe the transcriptional changes of fibroblast, endothelial cells and immune cells during the development of the disease and reveal new potential markers for early detection of PDAC
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