Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa

Abstract

Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma

“…This data is well in line with previous findings in colon cancer, showing that depletion of DCLK1 may inhibit NOTCH1 expression via upregulation of microRNA-144 (44). While concurrent decrease or increase of NOTCH pathway elements and DCLK1 was also reported in crypt epithelial stem cells following radiation injury (65), epithelial tuft cells (66), and enteric infection (67), further supporting the role of DCLK1 in NOTCH signaling regulation, additional studies are warranted to decipher the mechanism underlying a cross-talk between DCLK1 and NOTCH activities in HNSCC. Our analyses of a TMA containing HNSCC tumors obtained from 233 newly diagnosed and 40 recurrent patients revealed that high DCLK1 staining was strongly associated with decreased survival, confirming a previous report showing that DCLK1 mRNA level correlated with poor clinical outcome in a smaller cohort of NSCC patients that underwent surgery and postoperative radiotherapy (17).…”

Cranberry Polyphenols in Esophageal Cancer Inhibition: New Insights

“…Interestingly, polyphenols including picatannol, apigenin, chrysin and genistein upregulate NOTCH signaling to elicit anti-cancer effects via inhibition of cellular proliferation and migration [ 59 , 60 , 61 ]. NOTCH signaling is increased in progression from BE to EAC [ 62 , 63 , 64 , 65 ] and decreased NOTCH signaling inhibits EAC xenografts [ 66 ]. The ability of cranberry polyphenols to downregulate the intracellular domains of NOTCH1 and NOTCH2 is promising for targeting NOTCH-linked progression of BE to EAC ( Figure 10 ).…”

“…The ability of cranberry polyphenols to downregulate the intracellular domains of NOTCH1 and NOTCH2 is promising for targeting NOTCH-linked progression of BE to EAC ( Figure 10 ). Kunze et al recently showed that NOTCH2 and NOTCH3 were upregulated with progression to EAC in human tissues and expression of the intracellular domain of NOTCH2 led to increased dysplasia and decreased survival rates in the L2-Il1B mouse model of BE [ 65 ]. Our data show that the NOTCH signaling pathway is significantly modulated by C-PAC and AFG and that the canonical NOTCH target and transcriptional repressor HES1 [ 67 ] are downregulated by C-PAC and AFG in JHAD1 cells and by AFG in OE19 cells.…”

Tuft Cells and Their Role in Intestinal Diseases

“…TCs are massively expressed in locations of the ventricle, including epithelial areas of the cardia-near esophagus, where they seem to protect and repair the epithelium, for instance after acidic injury by gastro-esophageal reflux ultimately leading to Barrett’s adenocarcinoma ( 123 ). Recent insights kindle speculations about the genesis of sporadic intestinal tumors where TCs might be involved in the tumor etiology, although a direct involvement of TCs in the development of colorectal neoplasia (CRN) has not been reported.…”