Hall 123

Non-genetic contributions to pancreatic cancer initiation

Vishaka Gopalan

National Cancer Institute, NIH, Bethesda, MD, USA

Non-genetic transcriptional heterogeneity is a pervasive feature of any cell population owing to both the stochasticity of transcription as well as differences in the microenvironment faced by a cell in vivo. We set out to investigate whether such transcriptional variation may be large enough such that a small subset of cells may express genes related to cancer inititation before accumulating an oncogenic mutation.



We re-analyzed multiple pancreas and pancreatic adenocarcinoma single-cell RNA-seq datasets to find that a subset of pancreatic cells, called acinar cells, possess transcriptomes that are very different from an average acinar cell and do not express genes characteristic of acinar cells. Instead, these “edge” acinar cells, expressed genes characteristic of human embryonic pancreas genes as well as those related to pancreatic cancer progression. These cells thus represent a putative pre-cancerous population in the pancreas. We also found that the fraction of edge-like cells increased with age in healthy pancreatic tissue, even though they did not possess any clonal oncogenic mutations. This points to a key non-genetic factor in the known increase of pancreatic cancer risk with age. The fraction of edge-like cells is also significantly higher in human pancreatitis samples, suggesting a common cell state underlying both inflammation and recovery from injury, and pancreatic cancer. Finally, we find edge-like states in lung, liver, prostate, and colon tissues, suggesting that subpopulations of healthy cells across tissues can exist in pre-cancerous states prior to accumulating mutations.