RNA sequencing (RNA-SEQ) of WT and LFS patient specific iPSC derived pre-osteoblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE102732 | GEO | 2019/01/01
REPOSITORIES: GEO
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Project description:Purpose: To understand molecular and cellular effects of secreted sFRP2 to endothelial cells Methods: We performed RNA sequencing of 9 samples from HUVEC cultured in WT, sFRP2OE, LFS conditioned media for 16 hours Conclusion: apoptosis and angiogenetic molecular factors are activated in HUVEC by secreted sFRP2
2018-12-22 | GSE102729 | GEO
Project description:The purpose of this study was to identify genes that are misregulated in tomato pin-like apices. These apices could be induced either by the lfs mutation, or by treatment with the auxin polar transport inhibitor TIBA
2017-02-19 | GSE93540 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant and diverse tumor spectrum characterized by germline mutations in the TP53 tumor suppressor gene. To better understand how TP53 mutations predispose individuals with LFS to cancer development, we characterized tp53 R217H and R242H zebrafish lines as the first zebrafish p53 hotspot mutants (human R248 and R273H). These mutants have lost several key wildtype p53 functions and recapitulate many LFS phenotypes. Specifically, we have shown that the R217H and R242H alleles result in partial-to-no activation of key p53 target genes, are resistant to apoptosis in a dominant negative manner and exhibit a defective G1 cell-cycle checkpoint in vivo. The loss of these wildtype p53 functions predisposed the fish to develop spontaneous tumors as early as 6 months of age. Tumor histology resembles human sarcomas, a predominant LFS tumor type. tp53 R242H mutants developed tumors earlier with a higher lifetime incidence than tp53 null or R217H mutants, suggesting it is a more aggressive mutation, while the R217H allele may be hypomorphic. Additionally, we observed mutation-specific differences both in the tumor type and sex bias across tp53 null, R217H, and R242H genotypes with associated diverse transcriptomic and DNA methylome profiles, impacting metabolism, cell signalling, and biological macromolecule synthesis and degradation. These tp53 zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics, which may inform more tailored tumor surveillance approaches and novel therapeutic targets in LFS.
2024-05-29 | GSE268283 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant and diverse tumor spectrum characterized by germline mutations in the TP53 tumor suppressor gene. To better understand how TP53 mutations predispose individuals with LFS to cancer development, we characterized tp53 R217H and R242H zebrafish lines as the first zebrafish p53 hotspot mutants (human R248 and R273H). These mutants have lost several key wildtype p53 functions and recapitulate many LFS phenotypes. Specifically, we have shown that the R217H and R242H alleles result in partial-to-no activation of key p53 target genes, are resistant to apoptosis in a dominant negative manner and exhibit a defective G1 cell-cycle checkpoint in vivo. The loss of these wildtype p53 functions predisposed the fish to develop spontaneous tumors as early as 6 months of age. Tumor histology resembles human sarcomas, a predominant LFS tumor type. tp53 R242H mutants developed tumors earlier with a higher lifetime incidence than tp53 null or R217H mutants, suggesting it is a more aggressive mutation, while the R217H allele may be hypomorphic. Additionally, we observed mutation-specific differences both in the tumor type and sex bias across tp53 null, R217H, and R242H genotypes with associated diverse transcriptomic and DNA methylome profiles, impacting metabolism, cell signalling, and biological macromolecule synthesis and degradation. These tp53 zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics, which may inform more tailored tumor surveillance approaches and novel therapeutic targets in LFS.
2024-05-22 | GSE267760 | GEO
Project description:Here, we used single-cell RNA sequencing (scRNA-seq) to provide a high-resolution cellular taxonomy of freshly isolated primary human osteoblasts. Based on the gene expression patterns and cell lineage reconstruction, we identified three distinct clusters including preosteoblasts, mature osteoblasts, and an undetermined rare osteoblast subpopulation. Trajectory inference analysis suggested that the undetermined cluster may include osteoblast precursor cells which regulate the osteoblastogenesis process by giving rise to pre and mature osteoblasts. Investigation of the biological processes and signaling pathways enriched in each subpopulation revealed that in addition to bone formation, pre and undetermined osteoblasts may regulate both angiogenesis and hemopoiesis.
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Project description:Uterine scarring (US) is a common complication following uterine injury, characterized by abnormal wound healing in the endometrial or myometrial tissue. However, the underlying mechanisms contributing to scar formation remain unclear, impeding the development of effective drugs for US. Here, we identified that secreted frizzled-related protein 2 (sFRP2) is highly expressed in human and mouse uterine tissues with US, particularly in uterine fibroblasts (UFIBs). Using mouse models, we demonstrated that sFRP2 overexpression in the healthy uterus induced US features and exacerbated surgery-induced scarring, while sFRP2 knockout inhibited US development and scarring-transformation in UFIBs, highlighting the critical role of sFRP2 in mediating US. Mechanistically, sFRP2 promotes uterine scar formation by activating the non-canonical Wnt signaling pathway and calcium influx in UFIBs. Additionally, therapeutic potential of targeting sFRP2 was demonstrated by developing siRNA against sFRP2 and engineering delivery systems of lipid nanoparticles and injectable hydrogel. These siRNA therapies effectively inhibited sFRP2 expression, alleviated uterine scar formation, and improved pregnancy outcomes in mice, underscoring the great potential of sFRP2 as a promising therapeutic target for US.
2025-07-06 | GSE293910 | GEO
Project description:Diabetic foot ulcer (DFU) is a serious complication of diabetes mellitus, which causes great health damage and economic burden to patients. The pathogenesis of DFU is not fully understood.We screened wound healing-related genes using bioinformatics analysis, and full-thickness skin injury mice model and cellular assays were used to explore the role of target genes in diabetic wound healing. SFRP2 was identified as a wound healing-related gene, and the expression of SFRP2 is associated with immune cell infiltration in DFU. In vivo study showed that suppression of SFRP2 delayed the wound healing process of diabetic mice, impeded angiogenesis and matrix remodeling, and increased macrophage infiltration in wound tissues. In addition, suppression of SFRP2 enhanced M1 polarization in both the early and later stage of wound healing, and decreased M2 polarization in the later stage, which impeded the transition of M1 to M2 polarization of wound healing. Moreover, suppression of SFRP2 affected the transcriptome signatures-related to inflammatory response and energy metabolism at the early stage of wound healing. Extracellular flux analysis (EFA) showed that suppression of SFRP2 decreased mitochondrial energy metabolism and increased glycolysis in injury-related macrophages. Furthermore, suppression of SFRP2 inhibited transcriptome signaturesrelated to carbohydrate metabolism, lipid metabolism and amino acid metabolism, which consists the three main components of energy metabolism of macrophages. In conclusions, SFRP2 may function as a wound healing-related gene in DFU, and suppression of SFRP2 impaired diabetic wound healing by compromising the M1-to-M2 transition of macrophages and modulating the balance between mitochondrial energy metabolism and glycolysis.
2024-10-04 | GSE268760 | GEO
Project description:Diabetic foot ulcer (DFU) is a serious complication of diabetes mellitus, which causes great health damage and economic burden to patients. The pathogenesis of DFU is not fully understood.We screened wound healing-related genes using bioinformatics analysis, and full-thickness skin injury mice model and cellular assays were used to explore the role of target genes in diabetic wound healing. SFRP2 was identified as a wound healing-related gene, and the expression of SFRP2 is associated with immune cell infiltration in DFU. In vivo study showed that suppression of SFRP2 delayed the wound healing process of diabetic mice, impeded angiogenesis and matrix remodeling, and increased macrophage infiltration in wound tissues. In addition, suppression of SFRP2 enhanced M1 polarization in both the early and later stage of wound healing, and decreased M2 polarization in the later stage, which impeded the transition of M1 to M2 polarization of wound healing. Moreover, suppression of SFRP2 affected the transcriptome signatures-related to inflammatory response and energy metabolism at the early stage of wound healing. Extracellular flux analysis (EFA) showed that suppression of SFRP2 decreased mitochondrial energy metabolism and increased glycolysis in injury-related macrophages. Furthermore, suppression of SFRP2 inhibited transcriptome signaturesrelated to carbohydrate metabolism, lipid metabolism and amino acid metabolism, which consists the three main components of energy metabolism of macrophages. In conclusions, SFRP2 may function as a wound healing-related gene in DFU, and suppression of SFRP2 impaired diabetic wound healing by compromising the M1-to-M2 transition of macrophages and modulating the balance between mitochondrial energy metabolism and glycolysis.
2024-10-04 | GSE268759 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a rare, clinically and genetically heterogeneous inherited cancer syndrome. Most cases are due to mutations in TP53. CHK2 is a minor predisposing locus; we recently mapped a third locus to 1q23. In both TP53 and non-TP53 LFS, there is evidence for risk heterogeneity within and between kindreds, suggesting additional risk modifiers. Using BAC- and SNP-based microarrays, we performed genomic profiling of primary soft tissue sarcomas, osteosarcomas and matching constitutive samples of 10 LFS patients (6 with and 4 without TP53 mutations), to identify genome-wide patterns of copy number changes and loss-of-heterozygosity (LOH). Our complementing global approaches revealed several interesting patterns for TP53 and non-TP53 LFS tumors, including positive (1q/7, 3p/15, 4q/9q, 8q/19p, 9p/10q, 13/14 and 15q/18q) and negative (2q/9q, 3q/14q and 4q/6q) associations between chromosomal regions. The region containing the oncogene TWIST1 (7p21.1) was the most common gain independent of TP53 status and tumor type, while LOH of 8q11.2 with the tumor suppressor ST18 was the only region exclusively associated with non-TP53 soft tissue sarcomas. We resequenced known mutations in BRAF, KRAS and NRAS and identified somatic NRAS mutations in 2 of 10 tumors. TP53 and non-TP53 LFS tumors shared multiple hits in genes of the p53 and overlapping pathways. Although common dogma in cancer genetics holds that multiple hits in the same pathway are redundant and thus unlikely, we show that different combinations of genetic alterations in both TP53 and non-TP53 LFS tumors appear to act together in the p53 network in LFS tumorigenesis Keywords: Comparative genomic hybridization Using the Spectral Genomics dye-swap BAC arrays we studied 10 Li Fraumeni syndrome tumor cases
2008-07-16 | E-GEOD-8798 | biostudies-arrayexpress
Project description:Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used novel comparative transcriptomics analysis to identify genes that are uniquely overexpressed in a LFS GBM patient relative to a cancer compen-dium of 12,747 tumor RNA sequencing datasets including 200 GBMs. We then used ex vivo pa-tient derived organoid (PDO) viability assays with 4 patient derived cell lines to test efficacy of our identified target. Our comparative transcriptomics bioinformatics pipeline identified that STAT1 and STAT2 were significantly overexpressed in our patient indicating ruxolitinib, a Janus kinase 1 and 2 inhibitor, as a potential therapy. In our institutional high-grade glioma cohort of 45 patients, the LFS patient had the highest level of STAT1 and STAT2 expression. STAT1 and STAT2 expression levels in 4 cell lines derived from patients (including the LFS patient) corre-lated with levels identified in the respective parent tumors. Using 2D and 3D assays from pa-tient derived cells, our LFS patient of interest was among the most sensitive to ruxolitinib in comparison to patients with lower STAT1 and STAT2 expression levels. Additionally a sphe-roid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.
2021-12-02 | GSE188739 | GEO