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
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.
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