Project description:Clear cell sarcoma (CCS) of tendons and aponeuroses is a deadly soft-tissue malignancy resembling melanoma, with a predilection for young adults. EWS-ATF1, the fusion product of a balanced chromosomal translocation between chromosomes 22 and 12, is considered the definitional feature of the tumor. Conditional expression of the EWS-ATF1 human cDNA in the mouse generates CCS-like tumors with 100 percent penetrance. Tumors, developed through varied means of initiating expression of the fusion oncogene, model human CCS morphologically, immunohistochemically, and by genome-wide expression profiling. We also demonstrate that while fusion oncogene expression in later stages of differentiation can transform mesenchymal progenitor cells and generate tumors resembling CCS generally, expression in cells retaining stem cell markers permits the full melanoma-related phenotype. Nielsen et al. ("Molecular characterisation of soft tissue tumours: a gene expression study"; PMID 11965276) used microarray to compare a variety of soft-tissue neoplasms morphologically similar to clear cell sarcoma. In our study, we use their expression data (not previously submitted) in the profiling of our mouse mutant that models clear cell sarcoma. The mRNA profiles of a variety of soft-tissue neoplasm samples are examined by HEEBO microarrays. Included here are a total of 6 different types of tumors, and 5 of them have at least one biological replicate. The authors of "Molecular characterisation of soft tissue tumours: a gene expression study" (PMID 11965276) performed these microarray experiments, including data processing and normalization. We obtained these expression data, and used them to train a support vector machine, which was later used to characterize our mouse model of clear cell sarcoma (data submitted elsewhere).
Project description:Undifferentiated pleomorphic sarcoma (UPS) and related tumors are the most common type of soft tissue sarcoma. However, this spectrum of tumors has different etiologies with varying rates of metastasis and survival. Two dermal-based neoplasms in this class of pleomorphic sarcomas, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS), are challenging to differentiate at initial biopsy but vary significantly in prognosis. We performed single-cell transcriptomics on five AFX and PDS biopsy specimens as well as both single-cell and spatial transcriptomics on one PDS excision specimen to better characterize these tumors. The top differential genes between AFX and PDS were predictive of overall survival in 17 other cancers included in the Human Protein Atlas. Of these genes, COL6A3 and BGN predicted overall survival and metastasis-free survival in independent cohorts of 46 and 38 UPS tumors, respectively. COL6A3 was most predictive of overall survival in UPS patients and outperformed an established sarcoma prognostic gene panel at predicting metastasis in UPS.
Project description:Undifferentiated pleomorphic sarcoma (UPS) and related tumors are the most common type of soft tissue sarcoma. However, this spectrum of tumors has different etiologies with varying rates of metastasis and survival. Two dermal-based neoplasms in this class of pleomorphic sarcomas, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS), are challenging to differentiate at initial biopsy but vary significantly in prognosis. We performed single-cell transcriptomics on five AFX and PDS biopsy specimens as well as both single-cell and spatial transcriptomics on one PDS excision specimen to better characterize these tumors. The top differential genes between AFX and PDS were predictive of overall survival in 17 other cancers included in the Human Protein Atlas. Of these genes, COL6A3 and BGN predicted overall survival and metastasis-free survival in independent cohorts of 46 and 38 UPS tumors, respectively. COL6A3 was most predictive of overall survival in UPS patients and outperformed an established sarcoma prognostic gene panel at predicting metastasis in UPS.
Project description:Clear cell sarcoma (CCS) of tendons and aponeuroses is a deadly soft-tissue malignancy resembling melanoma, with a predilection for young adults. EWS-ATF1, the fusion product of a balanced chromosomal translocation between chromosomes 22 and 12, is considered the definitional feature of the tumor. Conditional expression of the EWS-ATF1 human cDNA in the mouse generates CCS-like tumors with 100 percent penetrance. Tumors, developed through varied means of initiating expression of the fusion oncogene, model human CCS morphologically, immunohistochemically, and by genome-wide expression profiling. We also demonstrate that while fusion oncogene expression in later stages of differentiation can transform mesenchymal progenitor cells and generate tumors resembling CCS generally, expression in cells retaining stem cell markers permits the full melanoma-related phenotype. Nielsen et al. ("Molecular characterisation of soft tissue tumours: a gene expression study"; PMID 11965276) used microarray to compare a variety of soft-tissue neoplasms morphologically similar to clear cell sarcoma. In our study, we use their expression data (not previously submitted) in the profiling of our mouse mutant that models clear cell sarcoma.
Project description:Analysis of undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma-like tumors from LSL-KrasG12D, p53Fl/Fl mouse model of soft tissue sarcoma. Murine soft tissue sarcomas (n = 17) were compared to normal muscle (n = 4). Tumors were isolated surgically from soft tissue sarcomas generated by conditional Kras and p53 alleles. Tumors were induced using an adenovirus expressing Cre recombinase. Normal muscle samples were isolated from mice of the same genotype without tumor induction.
Project description:This SuperSeries is composed of the following subset Series: GSE21122: Whole-transcript expression data for soft-tissue sarcoma tumors and control normal fat specimens GSE21123: Affymetrix SNP array data for soft tissue sarcoma samples Refer to individual Series
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—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.
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.
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.
Project description:Analysis of undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma like tumors from BrafCa, p53Fl/Fl mouse model of soft tissue sarcoma