Canonical Wnt Signaling Drives Tumor-Like Lesions from Sox2-Positive Precursors of the Murine Olfactory Epithelium

Engel, Nils W.; Ahlfeld, Julia; Wefers, Annika K.; Merk, Daniel J.; Ohli, Jasmin; Schüller, Ulrich

doi:10.1371/journal.pone.0166690

Cited by 7 publications

(8 citation statements)

References 44 publications

(41 reference statements)

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“…Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm of the sinonasal tract and presumed to arise from the olfactory epithelium [7,14]. Due to its rarity with an estimated incidence of 0.4 per million, accounting of only 2-3 percent of all sinonasal tumors [59], little is known about ONB genetics, molecular biology, or pathogenesis, as tumor tissue samples for comprehensive large-scale studies are limited.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation-based reclassification of olfactory neuroblastoma

et al. 2018

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Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.

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Section: Introductionmentioning

confidence: 99%

DNA methylation-based reclassification of olfactory neuroblastoma

et al. 2018

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“…This signaling pathway has been studied in the OE at the nasal pit stage in the context of facial development (Brugmann et al, 2007;Mani et al, 2010;Reid et al, 2011;Zhu et al, 2016) and at the postnatal and adult stages in the context of OE stem cell maintenance (Chen et al, 2014;Wang et al, 2011). However, it has not been studied at the stages in between, except in an ectopic activation study (see below; Engel et al, 2016).…”

Section: Wnt/bcat Signaling Maintains Fep Stemnessmentioning

confidence: 99%

FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area

2018

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The olfactory epithelium (OE) is a neurosensory organ required for the sense of smell. Turbinates, bony projections from the nasal cavity wall, increase the surface area within the nasal cavity lined by the OE. Here, we use engineered fibroblast growth factor 20 (Fgf20) knockin alleles to identify a population of OE progenitor cells that expand horizontally during development to populate all lineages of the mature OE. We show that these Fgf20-positive epithelium-spanning progenitor (FEP) cells are responsive to Wnt/β-Catenin signaling. Wnt signaling suppresses FEP cell differentiation into OE basal progenitors and their progeny and positively regulates Fgf20 expression. We further show that FGF20 signals to the underlying mesenchyme to regulate the growth of turbinates. These studies thus identify a population of OE progenitor cells that function to scale OE surface area with the underlying turbinates.

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“…By contrast, SOX11 was up-regulated in the wild type cells. Perturbation in the MAPK and Wnt signaling pathways that are activated in these cells may reflect the natural history of development of CCA (44) where SOX2 expression is upregulated in the precursor cell and supports self-renewal of the transformed cell (50)(51)(52). SOX11 plays a role in the tumor cell progression and in maintenance of the protein complex associated with the Wnt and other signaling pathways that mediate angiogenesis (53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Liver fluke granulin promotes exosome-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma

Arunsan

Chaidee

et al. 2019

Preprint

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Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with fish-borne liver flukes is a major risk factor for cholangiocarcinoma (CCA). The parasite secretes a growth factor termed liver fluke granulin (Ov-GRN-1), a homologue of the human progranulin (huPGRN), which contributes significantly to biliary tract fibrosis and morbidity during infection. Here, exosome-mediated transfer of mRNAs from the human cholangiocyte cell line (H69) was investigated following exposure to Ov-GRN-1, to naïve recipient H69 cells. To minimize the influence of endogenous huPGRN, the gene encoding huPGRN was inactivated using CRISPR/Cas9-based gene knock-out. Several huPGRN-depleted cell lines, termed DhuPGRN-H69, were established. These lines exhibited >80% reductions in levels of huPGRN transcripts and protein, both in gene-edited cells and within exosomes released by these cells. Profiles of exosomal RNAs (exRNA) from DhuPGRN-H69 for CCAassociated characteristics revealed a paucity of transcripts for estrogen-and Wnt-signaling pathways, peptidase inhibitors and tyrosine phosphatase related to cellular processes including oncogenic transformation. Several CCA-specific mRNAs including MAPK/AKT pathway members were induced by exposure to Ov-GRN-1. By comparison, estrogen, Wnt/PI3K and TGF signaling and other CCA pathway mRNAs were upregulated in wild type H69 exposed to Ov-GRN-1. Of these, CCA-associated exRNAs modified the CCA microenvironment in naïve recipient cells co-cultured with exosomes from DhuPGRN-H69 exposed to Ov-GRN-1, and induced translation of MAPK phosphorylation related-protein in naïve recipient cells comparing with control recipient cells. Exosome-mediated crosstalk in response to liver fluke granulin promoted a CCA-specific program through MAPK pathway which, in turn, established a CCAconducive disposition.

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Canonical Wnt Signaling Drives Tumor-Like Lesions from Sox2-Positive Precursors of the Murine Olfactory Epithelium

Cited by 7 publications

References 44 publications

DNA methylation-based reclassification of olfactory neuroblastoma

DNA methylation-based reclassification of olfactory neuroblastoma

FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area

Liver fluke granulin promotes exosome-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma

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