Dataset Information

Novel dedifferentiated liposarcoma xenograft models reveal PTEN down-regulation as a malignant signature and response to PI3K pathway inhibition.

ABSTRACT: Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care.

SUBMITTER: Smith KB

PROVIDER: S-EPMC3620414 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Novel dedifferentiated liposarcoma xenograft models reveal PTEN down-regulation as a malignant signature and response to PI3K pathway inhibition.

Smith Kathleen B KB Tran Linh M LM Tam Brenna M BM Shurell Elizabeth M EM Li Yunfeng Y Braas Daniel D Tap William D WD Christofk Heather R HR Dry Sarah M SM Eilber Fritz C FC Wu Hong H

The American journal of pathology 20130212 4

Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of ...[more]

PMID: 23416162

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Project description:BackgroundDedifferentiated liposarcoma (DDL), a member of malignant mesenchymal tumors, has a high local recurrence rate and poor prognosis. Pyroptosis, a newly discovered programmed cell death, is tightly connected with the progression and outcome of tumor.ObjectiveThe aim of this study was to explore the role of pyroptosis in DDL.MethodsWe obtained the RNA sequencing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression databases to identify different pyroptosis-related genes (PRGs) expression pattern. An unsupervised method for clustering based on PRGs was performed. Based on the result of cluster analysis, we researched clinical outcomes and immune microenvironment between clusters. The differentially expressed genes (DEGs) between the two clusters were used to develop a prognosis model by the LASSO Cox regression method, followed by the performance of functional enrichment analysis and single-sample gene set enrichment analysis. All of the above results were validated in the Gene Expression Omnibus (GEO) dataset.ResultsForty-one differentially expressed PRGs were found between tumor and normal tissues. A consensus clustering analysis based on PRGs was conducted and classified DDL patients into two clusters. Cluster 2 showed a better outcome, higher immune scores, higher immune cells abundances, and higher expression levels in numerous immune checkpoints. DEGs between clusters were identified. A total of 5 gene signatures was built based on the DEGs and divided all DDL patients of the TCGA cohort into low-risk and high-risk groups. The low-risk group indicates greater inflammatory cell infiltration and better outcome. For external validation, the survival difference and immune landscape between the two risk groups of the GEO cohort were also significant. Receiver operating characteristic curves implied that the risk model could exert its function as an outstanding predictor in predicting DDL patients' prognoses.ConclusionOur findings revealed the clinical implication and key role in tumor immunity of PRGs in DDL. The risk model is a promising predictive tool that could provide a fundamental basis for future studies and individualized immunotherapy.

Project description:BackgroundRetroperitoneal liposarcoma (RLPS) is a mesenchymal malignant tumor characterized by different degrees of adipocytic differentiation. Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are two of the most common subtypes of RLPS, exhibiting clear differences in biological behaviors and clinical prognosis. The metabolic features and genomic characteristics remain unclear.MethodsThis study employed lipidomic and RNA-seq analyses of RLPS tissues from 19 WDLPS and 29 DDLPS patients. Western blot and immunohistochemistry staining were performed to verify the tumor tissue protein levels of TIMP1, FN1, MMP11, GPNMB, and ECM1. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate different serum protein levels in 128 blood samples from patients with RLPS. Multivariate analysis was performed to identify the most crucial variables associated with overall survival (OS) and recurrence-free survival (RFS) of the RLPS patients.ResultsLipidomic analysis revealed a significant difference in lipid metabolism, particularly in phosphatidylcholines and triacylglycerides metabolism. RNA sequencing analysis revealed that 1,630 differentially expressed genes (DEGs) were significantly enriched in lipid metabolism, developmental process, and extracellular matrix (ECM) pathways. Integrated lipidomic and transcriptomic analysis identified 29 genes as potential biomarkers between WDLPS and DDLPS. Among the 29 DEGs, we found that TIMP1, FN1, MMP11, GPNMB, and ECM1 were increased in DDLPS tumor tissues than in WDLPS tumor tissues. The receiver operating characteristic (ROC) curve showed high specificity and sensitivity in diagnosing patients using a five-gene combination (AUC = 0.904). ELISA revealed a significant increase in the serum levels of ECM1 and GPNMB in patients with DDLPS compared to patients with WDLPS. ECM1 increased progressively across different FNCLCC Grades, correlating negatively with RFS (P = 0.043). GPNMB levels showed a negative correlation with OS (P = 0.019).ConclusionsOur study reveals different lipid metabolism, several transcriptional pathways between WDLPS and DDLPS, and examines several serum markers associated with the prognosis of RLPS. These findings provide a vital basis for future endeavors in diagnosing and predicting the prognosis of retroperitoneal liposarcoma with different differentiations.

Dataset Information

Novel dedifferentiated liposarcoma xenograft models reveal PTEN down-regulation as a malignant signature and response to PI3K pathway inhibition.

Publications

Novel dedifferentiated liposarcoma xenograft models reveal PTEN down-regulation as a malignant signature and response to PI3K pathway inhibition.

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