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Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma [scRNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281096 | GEO | 2024/11/08

REPOSITORIES: GEO

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Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma

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.

2024-11-10 | GSE281529 | GEO

Shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma of the extremities

Project description:Soft tissue sarcoma diagnostics and prognostics are challenging, particularly in highly malignant and pleomorphic subtypes such as undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS). We applied 32K BAC-arrays and gene expression profiling to 18 extremity soft tissue LMS and 31 extremity soft tissue UPS with the aim to identify molecular subtype signatures and genomic prognostic markers. Both the gains/losses and gene expression signatures revealed striking similarities between UPS and LMS, which were indistinguishable using unsupervised hierarchical cluster analysis and significance analysis for microarrays. Gene expression analysis revealed just 9 genes, among them Tropomyosin beta, that were differentially expressed. Loss of 4q31 (encompassing the SMAD1 locus), loss of 18q22 and tumor necrosis were identified as independent predictors of metastasis in multivariate stepwise Cox regression analysis. Combined analysis applying loss of 4q31 and 18q22 and presence of necrosis improved the area under receiver operating characteristic curve for metastasis prediction from 0.64 to 0.86. The extensive genetic similarities between extremity soft tissue UPS and LMS suggest a shared lineage of these STS subtypes and the new and independent genetic prognosticators identified hold promise for refined prognostic determination in high-grade, genetically complex STS. Genomic DNA was extracted from a total of 49 samples, 31 Undifferentiated pleomorphic Sarcomas and 18 Leiomyosarcomas. The DNA was labeled using Bioprime array CGH labeling kit (Invitrogen). Promega pooled male DNA was used as reference. Labeled DNA was hybridized onto BAC arrays containing ~32 000 BAC clones printed in singlets. BAC arrays were produced at the SWEGENE DNA Microarray Facility at Lund University.

2010-10-08 | E-GEOD-13775 | biostudies-arrayexpress

Shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma of the extremities

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Project description:In this study, we aimed to unravel the molecular underpinnings of pleomorphic dermal sarcomas (PDS), rare skin tumors often seen in sun-exposed regions. Using mass spectrometry, we examined proteomic profiles of 20 samples of normal healthy skin tissue (SNT), 27 malignant melanomas (MM), 20 cutaneous squamous cell carcinomas (cSCC), and 24 PDS. Our analysis aimed to: I.) Determine the potential cell of origin for PDS by correlating protein abundance to tumor purity using both RNA- and DNA-sequencing data. II.) Investigate receptor/ligand (R/L) interactions and their related pathways, highlighting distinct signaling differences between cSCC, MM, and PDS. III.) Identify differential protein markers, such as MAP1B_HUMAN, that can distinguish between cSCC, MM, and PDS. IV.) Explore proteins linked to immunosuppression in PDS, with a focus on those related to the negative regulation of interferon-gamma signaling. Together, this comprehensive proteomic exploration provides valuable insights into PDS and potential therapeutic targets.

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Single cell RNA sequencing data of Side Population and Non-Side Population tumor cells from a mouse model of undifferentiated pleomorphic sarcoma

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Undifferentiated pleomorphic sarcoma recapitulates the expressional profile of Subtype II Leiomyosarcoma

Project description:Background: Undifferentiated pleomorphic sarcoma (UPS), used to be called malignant fibrous histiocytoma (MFH), is a malignant soft tissue tumor of uncertain origin, and is characterized by morphology. UPS often share similar morphological characters with other sarcomas, especially Leiomyosarcoma. Leiomyosarcoma (LMS) is another malignant soft tissue sarcoma with complex genomic abnormalities, origin from smooth muscle. As a result, development of gene signature and/or biomarkers distinguishing UPS and LMS will definitely help the pathologist to precisely diagnose those patients. However, in the past, UPS was reported to be indistinguishable with LMS by genomic profiles. Methods and Results: In this study, 3’ end RNA Sequencing (3SEQ) was used to expression profile 6 UPS and 99 LMS cases. Overall, UPS was undistinguished with LMS by 3SEQ data, however, when we stratified LMS into three subtypes, UPS was shown to share similar expression pattern with Subtype II LMS, but had distinct molecular expression patterns with Subtype I and Subtype III LMS. Additional Immunohistochemistry staining by using LMS Subtype I and Subtype II markers validated that UPSs were positive for Subtype II marker ARL4C, but negative for Subtype I marker LMOD1. Furthermore, CD4 was shown to be significantly more highly expressed in UPS than LMS in both mRNA and protein levels. Conclusion: This study first reported that UPS shared similar gene expression pattern with subtype II LMS and UPS recapitulated the expression profiles of subtype II LMS. In this study, 3’ end RNA Sequencing (3SEQ) was used to expression profile 6 UPS and 99 LMS cases. In order to explore the molecular differences between UPS and LMS, We analyzed the expression data by SAMseq to identify the genes which were significantly differently expressed between UPS and LMS, between UPS and each LMS subtype.

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Characterization of a novel mouse model of undifferentiated pleomorphic sarcoma that is lymphocyte poor, macrophage rich, and resistant to immune checkpoint blockade

Project description:Sarcomas are rare, difficult to treat, mesenchymal lineage tumours that disproportionately affect children and young adults. Immunologically-based therapies have improved outcomes for numerous adult cancers, however, such approaches have proven ineffective for the majority of individuals with advanced sarcomas. Clinically relevant, immunologically-competent, and transplantable pre-clinical sarcoma models are needed in order to test and develop novel immunologically-based therapies for sarcoma. Herein we show that Cre- lox P-mediated simultaneous activation of Kras G12D , and deletion Trp53, in the hindlimb muscles of C57Bl/6 mice results in the development of highly penetrant, rapid onset undifferentiated pleomorphic sarcomas (UPS). The latter represents a model one of the most common human sarcoma subtypes both histologically and genetically. Furthermore, cell lines derived from the UPS tumors induced in C57Bl/6 mice can be transplanted into the hindlimbs or lungs of naïve, immune competent syngeneic mice. Immunological characterization of both the spontaneous and transplanted UPS tumours demonstrates an immunologically- ‘quiescent’ microenvironment, characterized by a paucity of lymphocytes and spontaneous adaptive immune pathways in addition to dense macrophage infiltrates. UPS cell line induced tumours demonstrate mildly increased lymphocytic infiltrates as compared with the spontaneous UPS tumours, furthermore, growth of transplanted UPS was unaltered in lymphocyte deficient hosts. Despite expression of PD-1 on the tumour infiltrating lymphocytes, UPS tumours were resistant to immunological checkpoint blockade. This syngeneic transplantable UPS model that recapitulates many of the immunological features of human UPS will prove invaluable for the preclinical development and evaluation of novel immunotherapeutic approaches for targeting sarcomas.

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Undifferentiated pleomorphic sarcoma recapitulates the expressional profile of Subtype II Leiomyosarcoma

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