The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis

Abstract

Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar-ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creER T2 -IRES-GFP mice. Furthermore, sorted Prrx1 + cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-Kras G12D/+ ;p53 fl/+ ;R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1-Sox9 axis may influence the emergence of acinar-ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate.

Cancer stem-like cells and thyroid cancer

“…2). Their findings agree with earlier studies reported by Ocaña et al (2012) and of Reichert et al (2013). The plasticity of CSCs and the EMT and MET processes has major implications for the therapeutic targeting of CSCs.…”

Cellular Plasticity and Heterogeneity in Pancreatic Regeneration and Malignancy

“…However, these findings do not rule out the possible existence of a subset of ductal cells with a higher degree of plasticity. In fact, recent findings from our labs have provided evidence for a rare subset of Prrx1+ ductal cells with a remarkable degree of sphere forming ability and features of progenitor cells [11] . In fact, Prrx1 ductal cells expanded markedly after cerulein-induced pancreatitis, consistent with a role in pancreatic regeneration after injury [11] .…”

175 The Ets-Transcription Factor Etv1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer

“…Cell lines were generated from PanIN-bearing LSL-Kras G12D/+ ;Cre mice (termed KC), 19,24 PDAC-bearing LSL-Kras G12D/+ ;p53 fl/+ ;Cre mice (termed KPfC), 25 and PDAC-bearing LSL-Kras G12D/+ ;p53 fl/+ ;Rosa26 YFP ;Cre (termed KPfCY). 26 In addition, cell lines from PDAC-bearing mice with a global SPARC deletion that have been previously described and characterized 27 were utilized (termed KPfC Sparc -/-).…”

“…Strikingly elevated levels of the Etstranscriptional factor Etv1 were observed in these three processes. 19 Approximately 30 Ets factors have been described in mammals, characterized by their conserved helix-turn-helix binding motif, called the Ets domain that binds to the GGAA/T core consensus sequence. 20 Ets factors have been classified into 9 subfamilies, with Etv1 and Etv5 belonging to the PEA3 subfamily.…”

“…18 Transcriptional factors that regulate convergence on ductal cell fate have remained elusive apart from Prrx1 and Sox9. 19 In an effort to identify transcriptional factors that may serve as "drivers" of pancreatic ductal fate, the transcriptional profile of cells derived from embryonic ductal pancreata, pancreatitis injury/regeneration model (acinar-ductal metaplasia), and early neoplasia (pancreatic epithelial neoplasia or PanIN) were analyzed. Strikingly elevated levels of the Etstranscriptional factor Etv1 were observed in these three processes.…”