Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA394698 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5831660.fastq.gz | Fastqsanger.gz | |||
| SRR5831661.fastq.gz | Fastqsanger.gz | |||
| SRR5831662.fastq.gz | Fastqsanger.gz | |||
| SRR5831663.fastq.gz | Fastqsanger.gz | |||
| SRR5831664.fastq.gz | Fastqsanger.gz |
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Project description:Background; Basal cell carcinoma (BCC) is the most common cancer in humans. The pathogenesis of BCC is associated with the sonic hedgehog (SHH) signaling pathway. Vismodegib, a smoothened inhibitor, that targets this pathway is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. Methods; We studied gene expression profiling of BCC tumour tissue coupled with laser capture microdissection to identify tumor specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. The expression of selected molecules was confirmed by quantitative RT-PCR (qRT-PCR) and by immunohistochemistry. The action of kinase inhibitors was examined on primary normal human epidermal keratinocytes. Results; We found a >250 fold change increase (false discovery rate <10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger staining of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Additionally, Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met, another receptor tyrosine kinase, inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 mRNA by approximately 60% and 20%, respectively (p<0.05). Conclusions; Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promotes keratinocyte proliferation. Furthermore, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients. Laser capture microdissection was performed on 5 cases of nodular/superficial BCC, 5 cases of infiltrative BCC.
2013-01-30 | E-GEOD-42109 | biostudies-arrayexpress
Project description:Background; Basal cell carcinoma (BCC) is the most common cancer in humans. The pathogenesis of BCC is associated with the sonic hedgehog (SHH) signaling pathway. Vismodegib, a smoothened inhibitor, that targets this pathway is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. Methods; We studied gene expression profiling of BCC tumour tissue coupled with laser capture microdissection to identify tumor specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. The expression of selected molecules was confirmed by quantitative RT-PCR (qRT-PCR) and by immunohistochemistry. The action of kinase inhibitors was examined on primary normal human epidermal keratinocytes. Results; We found a >250 fold change increase (false discovery rate <10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger staining of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Additionally, Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met, another receptor tyrosine kinase, inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 mRNA by approximately 60% and 20%, respectively (p<0.05). Conclusions; Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promotes keratinocyte proliferation. Furthermore, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients.
2013-01-30 | GSE42109 | GEO
Project description:Recent studies have demonstrated that ablative fractional laser (AFL) can inhibit the hedgehog pathway, enhance immune infiltration, and clear basal cell carcinomas (BCCs) in murine models. In this study, we applied RNA sequencing to further characterize the impact of AFL on the transcriptome of murine skin containing early-stage microscopic BCCs, contrasting it with the effects of the FDA approved hedgehog inhibitor vismodegib. Our results showed that BCC induction in murine skin was primarily linked to gene upregulation. Both AFL and vismodegib treatments were able to reverse this upregulation with vismodegib demonstrating superior performance by reversing the most genes (AFL: 59/277; vismodegib 180/277). Surprisingly, Ingenuity Pathway Analysis revealed that both treatments also caused considerable immune cell infiltration. Based on gene set enrichment analysis and cell type deconvolution, AFL treatment resulted in the largest immune cell recruitment, which for both treatments primarily consisted of infiltrating neutrophils, macrophages, and monocytes. In conclusion, the distinct effects observed in BCC skin following AFL and vismodegib treatment highlight key differences between the two interventions. Future applications of AFL or vismodegib treatments could leverage their individual effects, for example by combining AFL’s effects on the immune system with other topical treatments.
2024-11-28 | GSE254404 | GEO
Project description:BACKGROUND: Basal cell carcinoma (BCC) is the most common form of human cancer. Though the genetic mutation and subsequent aberrant signaling role of the Hedgehog pathway in BCC development is understood, little is known about the downstream genetic mechanisms underlying BCC growth. The characterization of molecular events would improve our understanding of carcinogenesis and may define new therapeutic intervention opportunities. OBJECTIVE: To identify differential gene expression associated with tumorigenesis promotion and to define common signaling pathways significant in BCC survival and growth. METHODS: Microarray analysis, using a 21K expanded sequence verified cDNA set was performed on tissues obtained from previously untreated patients undergoing Mohs surgical resection (8 superficial BCC, 8 nodular BCC, 7 morphea form, 8 normal skin). Significantly differentially expressed genes were identified by analysis of microarray results in various data sets and subsequently screened for signaling pathway involvement. Selected genes were validated using real-time PCR analysis using an expanded set of 31 BCC samples. RESULTS: The global gene expression profiles in BCCs and normal skin were distinguishable by unpaired T test. 2429 genes were at least 1.5 fold differentially expressed between BCC (all morphological types) and normal skin (p < 0.01). Multiple singaling pathways were activated, but the hedgehog, WNT, MAPK and calcium signal transduction pathways predominated. CONCLUSION: Our findings may have important implications for understanding the pathogenesis of BCC and suggest targeting of the WNT and MAPK pathways with therapeutic intervention. Keywords: disease state analysis
2006-12-15 | GSE6520 | GEO
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
| S-EPMC8784167 | biostudies-literature
Project description:Tumor heterogeneity and lack of knowledge about resistant cell states remain a significant barrier to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but nMRTF cell state and key factors driving its accumulation remain unknown. We have determined that AP-1 transcription factor activity is essential to maintain MRTF activation. Here, we treat a murine BCC cell line with small molecule AP-1 inhibitor and analyze chromatin accessibility profiles.
2020-08-25 | GSE156764 | GEO
Project description:Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model
| PRJNA160117 | ENA
Project description:Basal cell carcinoma (BCC), the most common human cancer results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited as in Bazex-Dupré-Christol syndrome (BDCS), an X-linked, dominant, cancer-prone type of genodermatosis. We discovered mutations in the ACTRT1 gene coding for actin-related protein T1 (Arp-T1) in 2/6 BDCS families. High-throughput sequencing revealed germline mutations in non-coding sequences surrounding ACTRT1 in the remaining four families. These mutations were located in transcribed enhancer regions (eRNA) and impaired enhancer activity and ACTRT1 expression. Furthermore, we found that Arp-T1 directly binds to the Gli1 promoter, thus inhibiting its expression, while loss of Arp-T1 led to activation of Hedgehog pathway in BDCS patients. Moreover, ACTRT1 reduced in vitro and in vivo proliferation of human BCC cell line and two tumor cell lines where Hedgehog signaling pathway is aberrantly activated (MDA-MB231 breast cancer and U2OS osteosarcoma cell lines). Our study highlights a novel causative mechanism in BCCs, demonstrates that ACTRT1 could act as a tumor suppressor beyond the context of BCC, and suggests that ACTRT1 and its regulatory regions may be potential therapeutic targets in cancerology.
2017-06-12 | E-MTAB-5597 | biostudies-arrayexpress
Project description:Activation of the Sonic hedgehog (Shh) signaling pathway due to Patched 1 (PTCH1) mutation is a key event in sporadic and familial basal cell carcinoma (BCC) development. To find out the specific pathway for therapeutic intervention, we developed a mouse BCC model by skin specific Ptch1 inactivation, and sought to identify novel Shh targets. We used microarrays to identify up-regulated genes in mouse BCC. We used microarrays to identify down-regulated genes in mouse BCC cell line by cyclopamine.
2018-01-15 | GSE20065 | GEO