Notch Signaling Mediates Differentiation in Barrett’s Esophagus and Promotes Progression to Adenocarcinoma

Kunze, Bettina; Wein, Frederik; Fang, Hsin-Yu; Anand, Akanksha; Baumeister, Theresa; Strangmann, Julia; Gerland, Sophie; Ingermann, Jonas; Münch, Natasha Stephens; Wiethaler, Maria; Sahm, Vincenz; Hidalgo-Sastre, Ana; Lange, Sebastian; Lightdale, Charles J.; Bokhari, Aqiba; Falk, Gary W.; Friedman, Richard A.; Ginsberg, Gregory G.; Iyer, Prasad G.; Jin, Zhezhen; Nakagawa, Hiroshi; Shawber, Carrie J.; Nguyen, TheAnh; Raab, William J.; Dalerba, Piero; Rustgi, Anil K.; Sepulveda, Antonia R.; Wang, Kenneth K.; Schmid, Roland M.; Wang, Yichen; Abrams, Julian A.; Quante, Michael

doi:10.1053/j.gastro.2020.04.033

Cited by 65 publications

(59 citation statements)

References 48 publications

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“…However, histopathologic scoring of inflammation at the SCJ of pL2.Dclk1.N2IC mice did not reveal significant changes (Supplemental Fig. 3 G), and analysis of immune cell populations from the cardia region of pL2.Dclk1 vs. pL2.Dclk1.N2IC mice showed no significant differences (not shown), similar to our recent data of pL2.Lgr5 tissues 10 . Thus, these data suggest that Notch activation in pL2.Dclk1.N2IC mice promotes epithelial-intrinsic signaling and expansion from Dclk1-positive cells 30 .…”

Section: Resultssupporting

confidence: 89%

“…1 A). Indeed, N2IC overexpression in Dclk1-positive tuft cells prominently accelerated BE progression, similar to Notch activation in Lgr5-positive gastric progenitor cells 10 . Histologic analysis confirmed the accelerated formation of metaplasia and dysplasia (Fig.…”

Section: Resultsmentioning

confidence: 78%

“…In a previous study, we showed that Notch 2 was highly upregulated in comparison to Notch 1 in the cardia of pL2-IL1b mice 10 . Furthermore, analysis of single-cell data on intestinal tuft cells 27 confirmed the expression of Notch pathway members in tuft cells, indicating that gastric tuft cells may contribute to BE pathogenesis.…”

Section: Resultsmentioning

confidence: 83%

“…Accordingly, active Notch signaling appears to promote intestinal tumor formation 6 , and we reported that Dll1-mediated activation of Notch signaling contributes to development of dysplasia at the SCJ in a BE mouse model 3 . However, the cell of origin for BE development remains unsettled, with squamous cells 7 , transitional basal cells 8 , squamous duct gland cells 9 , and gastric cardia cell origins 10 all proposed as possible candidates.…”

Section: Introductionmentioning

confidence: 99%

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

Kunze

Middelhoff

Maurer

et al. 2021

Sci Rep

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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.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Kunze

Middelhoff

Maurer

et al. 2021

Sci Rep

Self Cite

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“…ZFX plays a critical role in the maintenance of self-renewal in embryonic stem cells, and mutations have been linked to several cancers including colorectal, hepatocellular, and oral squamous carcinoma ( 28 , 29 ). Of special interest, the NOTCH signaling pathway maintains stem cells in the gastrointestinal tract and its dysregulation is implicated in the progression of both esophageal adenocarcinoma and squamous cell carcinoma ( 30 ). Taken together, there is a strong suggestion that the significant difference seen between males and females in incidence and survival of EC may be attributed to X-linked genes, particularly those that escape normal XCI.…”

Section: Discussionmentioning

confidence: 99%

Sex-Associated Gene Expression Alterations Correlate With Esophageal Cancer Survival

Weygant

Chang

Jackson

et al. 2020

Clin Transl Gastroenterol

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OBJECTIVES: Esophageal cancer (EC) is a significant cause of cancer death with 5-year survival of 10%–15% and males more frequently affected. Genetic evaluation for loci highlighting risk has been performed, but survival data are limited. The Cancer Genome Atlas (TCGA) data sets allow for potential prognostic marker assessment in large patient cohorts. The study aimed to use the TCGA EC data set to assess whether survival varies by sex and explore genetic alterations that may explain variation observed. METHODS: TCGA clinical/RNA-seq data sets (n = 185, 158 males/27 females) were downloaded from the cancer genome browser. Data analysis/figure preparation was performed in R and GraphPad Prism 7. Survival analysis was performed using the survival package. Text mining of PubMed was performed using the tm, RISmed, and wordcloud packages. Pathway analysis was performed using the Reactome database. RESULTS: In EC, male sex/high tumor grade reduced overall survival (hazard ratio = 2.27 [0.99–5.24] for M vs F and 2.49 [0.89–6.92] for low vs high grade, respectively) and recurrence-free survival (hazard ratio = 4.09 [0.98–17.03] for M vs F and 3.36 [0.81–14.01] for low vs high grade, respectively). To investigate the genetic basis for sex-based survival differences in EC, corresponding gene expression data were analyzed. Sixty-nine genes were dysregulated at the P < 0.01 level by the Wilcox test, 33% were X-chromosome genes, and 7% were Y-chromosome genes. DISCUSSION: Female sex potentially confers an EC survival advantage. Importantly, we demonstrate a genetic/epigenetic basis for these survival differences that are independent of lifestyle-associated risk factors overrepresented in males. Further research may lead to novel concepts in treating/measuring EC aggressiveness by sex.

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Multilevel Regulation of NF‐κB Signaling by NSD2 Suppresses Kras‐Driven Pancreatic Tumorigenesis

Feng,

Niu,

et al. 2024

Advanced Science

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Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36‐specific di‐methyltransferase that has been reported to play a crucial role in promoting tumorigenesis. Here, the study demonstrates that NSD2 acts as a putative tumor suppressor in Kras‐driven pancreatic tumorigenesis. NSD2 restrains the mice from inflammation and Kras‐induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2‐mediated H3K36me2 promotes the expression of IκBα, which inhibits the phosphorylation of p65 and NF‐κB nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF‐κB transcriptional activity. Furthermore, inhibition of NF‐κB signaling relieves the symptoms of Nsd2‐deficient mice and sensitizes Nsd2‐null PDAC to gemcitabine. Clinically, NSD2 expression decreased in PDAC patients and negatively correlated to nuclear p65 expression. Together, the study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study opens therapeutic opportunities for PDAC patients with NSD2 low/loss by combined treatment with gemcitabine and NF‐κBi.

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Notch Signaling Mediates Differentiation in Barrett’s Esophagus and Promotes Progression to Adenocarcinoma

Cited by 65 publications

References 48 publications

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

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

Sex-Associated Gene Expression Alterations Correlate With Esophageal Cancer Survival

Multilevel Regulation of NF‐κB Signaling by NSD2 Suppresses Kras‐Driven Pancreatic Tumorigenesis

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