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Mesenchymal loss of p53 alters stem cell capacity and models human soft tissue sarcoma traits [scRNA-seq]

ABSTRACT: Soft tissue sarcomas (STSs) are a heterogeneous group of tumors that originate from mesenchymal cells. p53 is frequently mutated in human STS. In this study, we found that the loss of p53 in mesenchymal stem cells (MSCs) mainly causes adult undifferentiated soft tissue sarcoma (USTS). MSCs lacking p53 show changes in stem cell properties, including differentiation, cell cycle progression, and metabolism. The transcriptomic changes and genetic mutations in murine p53-deficient USTS mimic those seen in human STS. Furthermore, single-cell RNA sequencing revealed that MSCs undergo transcriptomic alterations with aging—a risk factor for certain types of USTS—and that p53 signaling decreases simultaneously. Moreover, we found that human STS can be transcriptomically classified into six clusters with different prognoses, different from the current histopathological classification. This study paves the way for understanding MSC-mediated tumorigenesis and provides an efficient mouse model for sarcoma studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE226845 | GEO | 2023/03/21

REPOSITORIES: GEO

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Mesenchymal loss of p53 alters stem cell capacity and models human soft tissue sarcoma traits [bulk RNA-seq]

Project description:Soft tissue sarcomas (STSs) are a heterogeneous group of tumors that originate from mesenchymal cells. p53 is frequently mutated in human STS. In this study, we found that the loss of p53 in mesenchymal stem cells (MSCs) mainly causes adult undifferentiated soft tissue sarcoma (USTS). MSCs lacking p53 show changes in stem cell properties, including differentiation, cell cycle progression, and metabolism. The transcriptomic changes and genetic mutations in murine p53-deficient USTS mimic those seen in human STS. Furthermore, single-cell RNA sequencing revealed that MSCs undergo transcriptomic alterations with aging, which is a risk factor for certain types of UST, and that p53 signaling decreases simultaneously. Moreover, we found that human STS can be transcriptomically classified into six clusters with different prognoses, different from the current histopathological classification. This study paves the way for understanding MSC-mediated tumorigenesis and provides an efficient mouse model for sarcoma studies.

2023-03-08 | GSE226843 | GEO

Hypoxia and Intrinsic Transcriptomic Subtyping of Soft Tissue Sarcoma

Project description:The heterogeneity and multiple histological categories of soft tissue sarcoma (STS) underlie a need for better classification schemes to improve their management. As none are currently available, we aimed to derive hypoxia and intrinsic molecular subtype mRNA abundance signatures for localized soft tissue sarcoma. RNA sequencing was used to identify genes induced by hypoxia in seven STS cell lines.

2017-11-17 | E-MTAB-6087 | biostudies-arrayexpress

The Proteomic Landscape of Soft Tissue Sarcomas

Project description:Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of formalin-fixed paraffin embedded tumour specimens from 321 STS patients representing 11 histological subtypes.

2023-05-09 | PXD036226 | Pride

Full-length transcriptome sequencing reveals gene expression signatures in human soft tissue sarcomas

Project description:Soft tissue sarcomas (STSs) are heterogeneous malignancies derived from mesenchymal cells. Due to its rarity, heterogeneity, and limited overall response to chemotherapy, STSs represents a therapeutic challenge. Necroptosis is a novel therapeutic strategy for enhancing immunotherapy of cancer. Nevertheless, no research has explored the relationship between necroptosis-related genes (NRGs) and STSs.We performed full-length transcriptome analysis of four pairs of soft-tissue sarcomas and normal normal adjacent tissues. We further validated the expression level of necroptosis-related genes (NRGs) in these sample pairs.

2022-05-05 | GSE198568 | GEO

Metastatic and Nonmetastatic canine soft tissue sarcoma comparison

Project description:We hypothesize that there is a gene signature which will improve our ability to predict development of metastatic disease in STS patients. The objective of this study was to determine the feasibility of using cDNA microarray and quantitative real-time PCR (qRT-PCR) analysis to determine gene expression patterns in metastatic versus non-metastatic canine STSs, given the inherent heterogeneity of this group of tumors. Five STSs from dogs with metastatic disease were evaluated in comparison to eight STSs from dogs without metastasis. Tumor RNA was extracted, processed and labeled for application to the Affymetrix Canine Genechip 2.0 Array. Array fluorescence was normalized using D-Chip software and data analysis was performed with JMP/Genomics. Differential gene expression was validated using qRT-PCR. Over 200 genes were differentially expressed at a false discovery rate of 5%. Differential gene expression was validated for five genes upregulated in metastatic tumors. Quantitative RT-PCR confirmed increased relative expression of all five genes of interest in the metastatic STSs. Our results demonstrate that microarray and qRT-PCR are feasible methods for comparing gene signatures in canine STSs. Further evaluation of differences in gene expression between metastatic and non-metastatic STSs is likely to identify genes important in the development of metastatic disease and improve our ability to prognosticate for individual patients. Comparison of metastatic and non-metastatic (defined as no metastasis for at least one year) untreated tumor biopsies.

2011-02-01 | E-GEOD-24601 | biostudies-arrayexpress

Selective DNA-PK inhibition enhances chemotherapy and ionizing radiation activity in soft-tissue sarcomas

Project description:Purpose: Patients with advanced soft-tissue sarcomas (STSs) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase catalytic subunit (DNA-PK) is a multifunctional serine—threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining (NHEJ). Experimental design: To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacological inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen. Results: DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacological inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition. Conclusion: DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma

2023-09-25 | GSE243758 | GEO

KIF20A promotes the development of soft tissue sarcoma by activating the PI3K-AKT signaling pathway

Project description:Soft tissue sarcoma (STS) is a group of malignancies that can appear in any part of the body. The prognosis of STS patients remains unsatisfactory, mainly due to metastasis and recurrence. Upregulation of KIF20A is associated with poor prognosis of STS patients, but its downstream mechanism is unknown. In the present study, we found that downregulation of KIF20A in the STS cell line HT-1080 inhibits cell proliferation, migration, and invasion and induced cell apoptosis and G2/M arrest in vitro. In addition, downregulation of KIF20A in HT-1080 repressed tumorigenesis of STS in a xenograft mouse model. Pathway analysis showed, that downregulation of KIF20A led to suppression of downstream PI3K-AKT and NF-κB pathways. Specifically, the phosphorylation of AKT at Ser473 was inhibited. Taken together, our results indicate that KIF20A plays an important role in the development of STS by inhibiting cell proliferation, migration, invasion via the PI3K-AKT signaling pathway. Therefore, KIF20A is a potential therapeutic target in STS.

2020-11-23 | GSE140074 | GEO

Proteomic profiling of soft tissue sarcomas with SWATH mass spectrometry

Project description:In this work, we utilise sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for proteomic profiling of formalin fixed paraffin embedded (FFPE) specimens from a cohort of STS patients (n=36) across four histological subtypes (leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma). We quantified 2951 proteins in all cases and show that there is a significant enrichment of gene sets associated with smooth muscle contraction in leiomyosarcoma, RNA splicing regulation in synovial sarcoma and leukocyte activation in undifferentiated pleomorphic sarcoma. We further identified a subgroup of STS cases (independent of histological subtype) that have a distinct expression profile in a panel of 133 proteins, with worse survival outcomes when compared to the rest of the cohort. Our study highlights the value of comprehensive proteomic characterisation as a means to identify histotype-specific STS profiles that describe key biological pathways of clinical and therapeutic relevance; as well as for discovering new prognostic biomarkers in this group of rare and difficult-to-treat diseases.

2021-05-11 | PXD019719 | Pride

Metastatic and Nonmetastatic canine soft tissue sarcoma comparison

2011-02-01 | GSE24601 | GEO

Novel Properties of Side Population cells in Soft-tissue Sarcoma, and How They May Be Targeted to Develop Potential Therapies

Project description:Tumours contain heterogeneous cell populations. A population enriched in tumour-initiating potential has been identified in soft-tissue sarcoma (STS) by the isolation of side population (SP) cells. In this study, we compared the gene expression profiles of SP and non-SP cells in STS and identified Hedgehog (Hh) and Notch pathways as potential candidates for the targeting of SP cells. Upon verification of the activation of these pathways in SP cells, using primary tumor xenografts in NOD-SCID mice as our experimental model, we used the Hh blocker Triparanol and the Notch blocker DAPT to demonstrate that the suppression of these pathways effectively depleted the abundance of SP cells, reduced tumour growth, and inhibited the tumour-initiating potential of the treated sarcoma cells upon secondary transplantation. The data provide additional evidence that SP cells act as tumour initiating cells and points to Hh and Notch pathways as enticing targets for developing potential cancer therapies. We used microarrays to detail the difference in gene expressions between the side population cells in soft-tissue sarcoma in comparison to the bulk non-side-population cells.

2012-01-17 | GSE24199 | GEO

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