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Assessment of basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Blm-deficient Ptch1+/- mice

ABSTRACT: Basal cell carcinomas (BCCs) have relative genomic stability and relatively benign clinical behavior but whether these two are related causally is unknown. To investigate the effects of introducing genomic instability into murine BCCs, we have compared ionizing radiation-induced tumorigenesis in Ptch1+/- mice vs. that in Ptch1+/- mice carrying mutant Blm alleles. We found that BCCs in Ptch1+/- Blmtm3Brd/tm3Brd mice had a trend towards greater genomic instability as measured by array CGH and that these mice developed significantly more microscopic BCCs than did Ptch1+/- Blm+/tm3Brd or Ptch1+/- Blm+/+ mice. The mutant Blm alleles also markedly enhanced the formation of rhabdomyosarcomas (RMS), another cancer to which Ptch1+/- mice and PTCH1+/- (basal cell nevus syndrome) patients are susceptible. Highly recurrent but different copy number changes were associated with the two tumor types and included losses of chromosomes 4 and 10 in all BCCs and gain of chromosome 10 in 80% of RMSs. Loss of chromosome 11 and 13, including the Trp53 and Ptch1 loci respectively, occurred frequently in BCCs, suggesting tissue-specific selection for genes or pathways that collaborate with Ptch deficiency in tumorigenesis. Despite the quantitative differences, there was no dramatic qualitative difference in the BCC or RMS tumors associated with the mutant Blm genotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE19880 | GEO | 2010/01/14

SECONDARY ACCESSION(S): PRJNA121981

REPOSITORIES: GEO

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Assessment of basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Blm-deficient Ptch1+/- mice

Project description:Basal cell carcinomas (BCCs) have relative genomic stability and relatively benign clinical behavior but whether these two are related causally is unknown. To investigate the effects of introducing genomic instability into murine BCCs, we have compared ionizing radiation-induced tumorigenesis in Ptch1+/- mice vs. that in Ptch1+/- mice carrying mutant Blm alleles. We found that BCCs in Ptch1+/- Blmtm3Brd/tm3Brd mice had a trend towards greater genomic instability as measured by array CGH and that these mice developed significantly more microscopic BCCs than did Ptch1+/- Blm+/tm3Brd or Ptch1+/- Blm+/+ mice. The mutant Blm alleles also markedly enhanced the formation of rhabdomyosarcomas (RMS), another cancer to which Ptch1+/- mice and PTCH1+/- (basal cell nevus syndrome) patients are susceptible. Highly recurrent but different copy number changes were associated with the two tumor types and included losses of chromosomes 4 and 10 in all BCCs and gain of chromosome 10 in 80% of RMSs. Loss of chromosome 11 and 13, including the Trp53 and Ptch1 loci respectively, occurred frequently in BCCs, suggesting tissue-specific selection for genes or pathways that collaborate with Ptch deficiency in tumorigenesis. Despite the quantitative differences, there was no dramatic qualitative difference in the BCC or RMS tumors associated with the mutant Blm genotype. We investigated the effect of Blm deficiency on ionizing radiation-induced basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice. Six BCC and five RMS samples were obtained from separate mice. Liver tissue from each mouse was used as the normal reference.

2010-05-15 | E-GEOD-19880 | biostudies-arrayexpress

Deep Sequencing the microRNA profile in rhabdomyosarcoma reveals down-regulation of miR-378 family members

Project description:Rhabdomyosarcoma (RMS) is a highly malignant tumour accounting for nearly half of soft tissue sarcomas in children. Altered miRNA levels have been reported in human cancers, including RMS. Using deep sequencing technology, a total of 685 miRNAs were investigated in a group of alveolar RMSs (ARMSs), embryonal RMSs (ERMSs) as well as in normal skeletal muscle (NSM). Bioinformatics pipelines were used for miRNA target prediction and clustering analysis. Ninety-seven miRNAs were significantly deregulated in ARMS and ERMS when compared to NSM. MiR-378 family members were dramatically decreased in RMS tumour tissue and cell lines. Interestingly, members of the miR-378 family presented as a possible target the insulin-like growth factor receptor 1 (IGF1R), a key signalling molecule in RMS.

2015-01-28 | E-MTAB-3246 | biostudies-arrayexpress

Modeling pleomorphic rhabdomyosarcoma in mice

Project description:Here we used Ptch1+/-/ETV7TG/+/- mice with enhanced incidence of RMS to generate a model of pleomorphic RMS driven by haploinsufficiency of the lysosomal sialidase Neu1. These tumors share features and location with human RMS.

2022-09-26 | GSE212378 | GEO

Testing the impact of Type I Restriction Modification Systems on Gene Expression in Uropathogenic Escherichia coli

Project description:Background: DNA methylation influences transcriptional regulation, and therefore cellular phenotype, across all domains of life. The regulatory role of DNA methylation and other epigenetic marks also extends to virulence; both orphan methyltransferases and those from restriction modification systems (RMSs) have been co-opted to regulate virulence in many bacteria. However, functional characterisation of DNA methylation mediated by archetypal Type I RMSs remains limited. Results: We elucidated the methylation specificity of the Type I RMS in UTI89, a prototypical cystitis strain of E. coli. Deletion of this RMS led to loss of methylation of >750 sites across the genome but no detectable effect on gene expression, virulence, or growth in a screen of 1190 conditions. Similarly, deletion of the endogenous Type I RMS in two other E. coli strains with different methylation specificities also had no effect on gene expression or any growth phenotype. Finally, introduction of these two different RMSs into UTI89 also resulted in no detectable change in gene expression or growth phenotypes. These results stand in sharp contrast with many reports of RMSs regulating gene expression in other bacteria, leading us to propose the concept of “regulation avoidance” for these E. coli Type I RMSs. We hypothesize that regulation avoidance is a consequence of evolutionary adaptation of both the RMSs and the E. coli genome. Conclusions: Our results provide a clear and currently rare example of regulation avoidance for Type I RMSs in multiple strains of E. coli, further study of which may provide deeper insights into the evolution of gene regulation and horizontal gene transfer.

2021-07-01 | GSE165421 | GEO

Differences in gene expression between ASP WT and ASPcKO tumors

Project description:To further examine the consequences of Pten loss in a Hedgehog driven, murine FN-RMS, we used microarrays to determine the transcriptomic differences between our aP2-Cre;SmoM2 FN-RMS model (Hatley et al. 2012, Cancer Cell) and aP2-Cre; SmoM2; Pten flox/flox FN-RMSs.

2021-08-24 | GSE166809 | GEO

Quantitative assessment of transcriptomic differences between ASPcKO and ASPcKOP7cKO flow cytometry-sorted murine FN-RMSs by RNA sequencing

Project description:We report the transcriptomic differences between ASPcKO and ASPcKOP7cKO flow cytometry-sorted FN-RMSs by RNA sequencing. The goal of this study is to determine what role Pax7 loss has on Pten-deficient, Hedgehog-activated murine FN-RMS tumors. These results provide implications for the transcriptomic program driven by Pax7 in dictating FN-RMS tumor fate.

2021-08-24 | GSE166808 | GEO

Mus musculus

Project description:Assessment of basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Blm-deficient Ptch1+/- mice

| PRJNA121981 | ENA

Implication of Nos2 inactivation on genomic changes in Ptch1+/- medulloblastomas (array-CGH)

Project description:The Ptch1+/- strain constitues an established mouse model for the Shh-driven type of medulloblastoma. Combined Ptch1+/- Nos2-/- mice show a two-fold increased incidence for this tumor. Here, the impact of Nos2 inactivation on copy number alterations during medulloblastoma development was investigated by array-based comparative genomic hybridization (arrayCGH) of tumor samples from both genotypes. Medulloblastoma samples from five Ptch1+/- and seven compound Ptch1+/- Nos2-/- mice were analyzed. Cy5-labeled tumor DNA was combined with corresponding Cy3-labeled reference healthy wildtype genomic DNA to receive either sex-matched sample pairs or pairs of different gender for internal negative or positive control.

2011-12-01 | E-GEOD-29199 | biostudies-arrayexpress

Sensitive detection of radiation-induced medulloblastomas after acute or protracted gamma ray exposures in Ptch1 heterozygous mice using a radiation-specific molecular signature

Project description:Recent studies have further heightened awareness of the risk of radiation-induced cancer after diagnostic radiology imaging, in particular, brain cancer following childhood CT scans. One feature of Ptch1+/- mice is that they are sensitive to radiation-induced medulloblastomas (an embryonic cerebellar tumor) during a narrow time window centered on the days around birth. The dynamics of how dose-protraction interacts with such narrow windows of sensitivity in individual tissues is still unknown. Using medulloblastomas from irradiated Ptch1+/- mice on a hybrid C3H × C57BL/6 F1 background, we have previously shown that the alleles retained on chromosome 13 (which harbors the Ptch1 gene) reveal two major mechanisms of loss of the wildtype allele. The loss of parental alleles from the telomere extending up to or past the Ptch1 locus by recombination (spontaneous-type) accounts for almost all medulloblastomas in unirradiated mice, while tumors in irradiated mice often exhibited interstitial deletions which start downstream of the wildtype Ptch1 and extend up varying lengths towards the centromere (radiation-type). Here, Ptch1+/- mice were exposed to an acute dose of 0.1 or 0.5 Gy gamma rays in utero or postnatally, or the same radiation doses protracted over a 4-day period, and were monitored for medulloblastoma development. The results show dose-dependent and age-dependent induction of radiation-type tumors; that the size of the radiation-induced deletion differs with the dose-rate; and, that tumor latency may be related to the size of the deletion. The radiation signature allows for unique mechanistic insight into the action of radiation to induce DNA lesions with known causal relationship to a specific tumor type, particularly for doses and dose-rates more relevant to diagnostic radiology imaging and accidental exposure of populations to radiation.

2017-04-26 | GSE81319 | GEO

Rhabdomyosarcomas are oncogene addicted to the activation of AVIL

Project description:Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, MARS-AVIL formed by chromosomal inversion in RMS. Suspecting that forming a fusion with a housekeeping gene may be one of the mechanisms to dysregulate an oncogene, we investigated AVIL expression and its role in RMS. We first showed that MARS-AVIL translates into an in-frame fusion protein, which is critical for the RMS cell tumorigenesis. Besides forming a gene fusion with the housekeeping gene, MARS, the AVIL locus is often amplified, and its RNA and protein expression is overexpressed in the majority of RMSs. Tumors with AVIL dysregulation exhibit evidence of oncogene addiction: silencing MARS-AVIL in cells harboring the fusion, or silencing AVIL in cells with AVIL overexpression, nearly eradicated the cells in culture, as well as inhibited in vivo xenograft growth in mice. Conversely, gain-of-function manipulations of AVIL led to increased cell growth and migration, enhanced foci formation in mouse fibroblasts, and most importantly transformed mesenchymal stem cells in vitro and in vivo. Mechanistically, AVIL seems to serve as a converging node functioning upstream of two oncogenic pathways, PAX3-FOXO1 and RAS, thus connecting two types of RMS associated with these pathways. Interestingly, AVIL is overexpressed in other sarcoma cells as well, and its expression correlates with clinical outcomes, with higher levels of AVIL expression being associated with worse prognosis. AVIL is a bona fide oncogene in RMS, and RMS cells are addicted to its activity.

2022-06-07 | GSE180837 | GEO

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