Dataset Information

Natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis.

ABSTRACT: Cancer predisposing allelic variants have shown to be notoriously difficult to identify by conventional GWA studies. Searching for preferential co-occurrence with defined somatically acquired oncogenic lesions can significantly contribute to the identification of such alleles1. We here show that a natural Wnt-7b allelic variant in the mouse, which is not associated with increased tumour susceptibility, strongly synergizes with loss of the Cdkn2ab tumour suppressor locus in cancer development. Previously, we reported that Cdkn2ab-/- mice, generated from 129P2 ES cells develop skin carcinomas 2. The incidence of these carcinomas dropped gradually in the course of backcrossing to the FVB/N background suggesting that one or more 129P2 alleles cooperate with Cdkn2ab deficiency in skin carcinogenesis. Here we show that this skin cancer phenotype is linked to a 20Mb region of 129P2 chromosome 15 harboring the Wnt7b and Pdgfb genes. Both Wnt7b and Pdgfb are preferentially expressed from the 129P2 allele in skin carcinomas and derived cell lines. ChIPseq analysis showed enrichment of H3K27-Ac, a mark for active enhancers, in the 5’ region of the Wnt7b 129P2 gene. Moreover, the Wnt7b 129P2 allele appeared sufficient to cause in vitro transformation and anchorage-independent growth of Cdkn2ab deficient cell lines. Further we show that Wnt7b contributes to transformation through Cdk6 activation. Our observations imply that normally occurring variations in Wnt expression can elicit transformation of cells upon Cdkn2ab locus loss and point to a critical role of the Cdkn2ab locus in keeping the oncogenic potential of physiological levels of Wnt signaling in check. Consequently, it will be worthwhile to explore whether human tumours that show loss of CDKN2ab are associated with distinct allelic variants causing enhanced WNT signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE125885 | GEO | 2019/02/12

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. The brain microvascular fragments were isolated from mice with different genotypes, each represented by 3-4 biological replicates. Genotypes 1-2: Platelet derived growth factor-B (PDGF-B) retention-motif knockout (pdgfbret/ret) represent the pericyte-deficient situation, and the heterozygous mice (pdgfbret/+) are used as controls. Genotypes 3-4: Hypomorphic PDGF-B mutants that rescue pdgfb-/- null mice, in which a one copy of a conditionally silent human PDGF-B transgene targeted to the Rosa 26 locus (R26P) is turned on by endothelial-specific expression of Cre recombinase. In this data set these mice are named as Tie2Cre, R26P+/0, pdgfb-/- (representing the pericyte-deficient situation). Mice wt for pdgfb (pdgfb+/+) and carrying one silent copy of R26P (R26P+/0), are used as controls. Genotype 5: Adult Notch3+/+ wildtype (WT).

Dataset Information

Natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure