Wnt signaling potentiates nevogenesis

Abstract

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescenceassociated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescenceassociated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.

A Systematic Evaluation of Methods for Tailoring Genome-Scale Metabolic Models

“…We built cell line specific models using RNA-Seq data (Bürckstümmer et al, 2013; Di Ruscio et al, 2013; Pawlikowski et al, 2013; Zhang et al, 2015) to specify active genes in each cell line. Active genes are identified by many algorithms based on a quantitative threshold of expression.…”

“…The mRNA-sequencing datasets (Bürckstümmer et al, 2013; Di Ruscio et al, 2013; Pawlikowski et al, 2013; Zhang et al, 2015) were downloaded, and Trimmomatic (Bolger et al, 2014) was used to trim low quality reads. The reads were aligned to the GRCh38 reference human genome using STAR (Dobin et al, 2013) (4 STAR parameters were set: ‘–outSAMstrandField intronMotif’, ‘–outFilterType BySJout’, ‘–outFilterIntronMotifs RemoveNoncanonicalUnannotated’, ‘–outSAMtype BAM SortedByCoordinate’, others are set as default), and then quantified using Cufflinks with all parameters set as defaults (Trapnell et al, 2011), using the unit of fragments per kilobase of exon per million fragments (FPKM) for all genes.…”

“…The mRNA-sequencing datasets were acquired from previous publications (Bürckstümmer et al, 2013; Di Ruscio et al, 2013; Pawlikowski et al, 2013; Zhang et al, 2015) and genome-scale CRISPR-Cas9 knockout screens were obtained from (Shalem et al, 2014; Wang et al, 2015, 2014). Matlab code for running extraction methods and performing analysis are provided in Data S1 (see also https://github.com/LewisLabUCSD/Context_Specific_Models_from_GeMS ).…”

Altered Expression and Splicing of ESRP1 in Malignant Melanoma Correlates with Epithelial–Mesenchymal Status and Tumor-Associated Immune Cytolytic Activity

“…2C). Additionally, publicly accessible RNA-Seq data of independently derived melanocyte specimens (NCBI GEO GSE46805 and GSE33092) all show truncated ESRP1 expression in melanocytes (33,34).…”

Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction

“…Recent reports have demonstrated that melanocytes expressing senescence markers accumulate in human skin, and this was significantly associated with increased facial wrinkles, higher perceived age and age‐associated elastin morphology in the papillary dermis (Waaijer et al , , ). Interestingly, expression of p16 INK4A , a known marker of senescence, was shown to co‐localise almost exclusively to melanocytes in the epidermis, suggesting that melanocytes represent the major p16 INK4A senescent cell population in the epidermis of human skin (Waaijer et al , , ; Pawlikowski et al , ). This observation is surprising given that fully differentiated melanocytes have an extremely low replicative capacity (Jimbow et al , ; Taylor et al , ).…”