Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of only 11%, due, in part, to late diagnosis, making the need to understand early events in tumorigenesis critical. Acinar-to-ductal metaplasia (ADM), when not resolved, is a PDAC precursor. Recently, we showed that ADM is constituted by a heterogenous population of cells, including hormone-producing enteroendocrine cells (EECs: gamma, delta, epsilon, and enterochromaffin cells). In this study, we employed histopathological techniques to identify and quantify the abundance of EEC subtypes throughout pancreatic tumorigenesis in mouse models and human disease. We found that EECs are most abundant in ADM and significantly decrease with lesion progression. Co-immunofluorescence identifies distinct lineages and bihormonal populations. Evaluation of EEC abundance in mice lacking Pou2f3 demonstrates that the tuft cell master regulator transcription factor is not required for EEC formation. We compared these data to human neoplasia and PDAC and observed similar trends. Lastly, we confirm that EECs are a normal cellular compartment within the murine and human pancreatic ductal trees. Altogether, these data identify EECs as a cellular compartment of the normal pancreas, which expands early in tumorigenesis and is largely lost with disease progression.

Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer

“…In contrast, we found no islet hormone expression in the mTC-derived mNECs in the KPF-P2f3T mouse. These data indicated that mNECs in our KF-P2f3T neoplasia model, but not in our KPF-P2f3T carcinoma model, are likely EECs, similar to those found in other models of pancreatic disease 17, 21, 22 .…”

“…While we have found mNECs in the pancreata of both neoplasia and carcinoma models, they appear to have distinct cellular origins. We confirmed that mNECs and mTCs in both models derive from acinar cells 17,22 using an acinar cell lineage trace of Pt1fa Cre/+ ; ROSA26 LSL-YFP/+ in neoplasia and carcinoma models. We show co-localization with GFP (to mark acinar cells and progeny) and either Cox1 (mTCs) or Syp (mNECs) for both models (Supp.…”

“…EECs share a seemingly similar fate as mTCs in that they are present at early stages of ADM but diminish as PDA progresses to dedifferentiated carcinoma 22 . Our data support an association of EECs with early oncogenesis as they are largely confined to our neoplasia model and absent in our carcinoma model.…”

“…Pancreatic tumor cells expressing neural/neuroendocrine markers in human PDA and are comprised of two different subsets: neuroendocrine-like or enteroendocrine cells (EECs) 7, 22 and neural-like progenitor cells (NRPs) 21 , the latter of which is associated with poor outcomes. EECs express hormone markers typically confined to islet cells 17, 21, 22 , whereas NRPs express markers of neural progenitor cells, including Nrxn3 21 . We found that mNECs in Kras G12D -driven neoplasia arise independent of mTCs and take on an islet hormone-positive EEC identity, consistent with previous data showing EECs in metaplasia are independent of mTCs and do not depend on Pou2f3 to develop 22 .…”

It is better to light a candle than to curse the darkness: single-cell transcriptomics sheds new light on pancreas biology and disease

“…Metaplasia-specific factors were identified including transcription factors such as Onecut2 —previously identified as a master regulator of prostate cancer 31. Six metaplastic cell types/states were characterised including gastric pit-like cells ( Gkn1+Tff1+Muc5ac+ ) and chief-like cells ( Pga5+Pgc +), tuft cells and enteroendocrine cells (consistent with prior studies,20 32 33), senescent cells and proliferative metaplastic cells (figure 2). Lineage trajectory analysis of this dataset suggested that the gastric-like population and tumour can arise through distinct cell states, but it is still not clear which metaplastic cell types become malignant.…”