A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and pancreatic ductal adenocarcinoma

About this Class

The intrinsic stochasticity of transcription leads to gene expression variation across cells in a clonal cell population. The expression variation can translate into phenotypic variation that can persist through several rounds of cell division. In the context of tumor initiation, such inter-cell variation within a normal tissue can cause a fraction of cells to assume “edge” transcriptional states that are primed for a transition toward malignancy. In such a framework, oncogenic mutations can interact with transcriptional priming to lead to malignant transformation. We developed a two-stage test to find such transcriptional states in single-cell RNA-seq data from healthy pancreatic tissues and pancreatic ductal adenocarcinoma (PDAC) tumors. We found a subset of non-malignant pancreatic acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes are highly diverged from a typical normal acinar cell and are much closer to a malignant state.  Gene expression changes in AE cells recapitulate known gene expression changes during PDAC initiation and pancreatitis, which provides a common transcriptomic basis between pancreatitis and PDAC. Most strikingly, the fraction of AE-like cells increased with age, with no underlying mutational basis. Coupled with our observation that gene expression changes in AE cells in mice mirrored those during Kras-G12D induction, our findings point to a strong contribution of AE cells, and non-genetic expression heterogeneity in general, to PDAC initiation. WebEx Link: https://cbiit.webex.com/cbiit/j.php?MTID=med94a210a2c7c80e76396498a7f7bf7b  Meeting number: 172 241 0782 Meeting PW: jjM4nAT3e@4 Audio-only Call-in #: 1-650-479-3207 (Access code: 172 241 0782)