Abstract:The human cancer/testis antigen LIPI is highly expressed in Ewing family tumours and can be easily detected by RT-PCR or quantitative RT-PCR. LIPI might be an interesting target for the development of future diagnostic tools or treatment strategies.
“…2C; Staege et al 2004). Remarkably, the membrane-associated phospholipase A1 b LIPI that has been reported recently to be a specific ESFT marker (Foell et al 2008) was induced in hpMSCs but not in adult MSCs (Fig. 2C).…”
Section: The Response Of Pediatric Mscs To Ews-fli-1 Differs From Thamentioning
Cancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%-90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype.[Keywords: Ewing sarcoma; SOX2; cancer stem cells; mesenchymal stem cells; miRNA145; reprogramming] Supplemental material is available at http://www.genesdev.org.
“…2C; Staege et al 2004). Remarkably, the membrane-associated phospholipase A1 b LIPI that has been reported recently to be a specific ESFT marker (Foell et al 2008) was induced in hpMSCs but not in adult MSCs (Fig. 2C).…”
Section: The Response Of Pediatric Mscs To Ews-fli-1 Differs From Thamentioning
Cancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%-90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype.[Keywords: Ewing sarcoma; SOX2; cancer stem cells; mesenchymal stem cells; miRNA145; reprogramming] Supplemental material is available at http://www.genesdev.org.
“…To evaluate the immunogenic and therapeutic potential of CTA in EFT, T cells were generated with specificity for the known CTA lipase I alias membrane-associated phospholipase A1-β (LIPI) characteristically expressed in EFT [10][11][12] and having probably important roles in pathophysiology in EFT via production of lysophosphatidic acid. 13 Due to its putative role for oncogenesis and proliferation and its selective expression LIPI represents an excellent immunotherapeutic target.…”
“…Among them we found not only many established CSGs such as LIPI for Ewing sarcoma, 21
PRAME for neuroblastoma 22,23 and members of the MAGE -family for germinoma, 24 neuroblastoma, 25 synovial sarcoma, 26 multiple myeloma, 27 diffuse large B cell lymphoma (DLBCL), 28 and osteosarcoma, 29 but also many novel candidates of which some appear to be suitable for targeting multiple cancer entities (Figure 2, Supplementary Table 5, Supplementary Figure 1). 10.1080/2162402X.2018.1481558-F0002Figure 2.Overexpressed CSGs in multiple cancer entities identified with RAVEN.…”
Immunotherapy can revolutionize anti-cancer therapy if specific targets are available. Immunogenic peptides encoded by cancer-specific genes (CSGs) may enable targeted immunotherapy, even of oligo-mutated cancers, which lack neo-antigens generated by protein-coding missense mutations. Here, we describe an algorithm and user-friendly software named RAVEN (Rich Analysis of Variable gene Expressions in Numerous tissues) that automatizes the systematic and fast identification of CSG-encoded peptides highly affine to Major Histocompatibility Complexes (MHC) starting from transcriptome data. We applied RAVEN to a dataset assembled from 2,678 simultaneously normalized gene expression microarrays comprising 50 tumor entities, with a focus on oligo-mutated pediatric cancers, and 71 normal tissue types. RAVEN performed a transcriptome-wide scan in each cancer entity for gender-specific CSGs, and identified several established CSGs, but also many novel candidates potentially suitable for targeting multiple cancer types. The specific expression of the most promising CSGs was validated in cancer cell lines and in a comprehensive tissue-microarray. Subsequently, RAVEN identified likely immunogenic CSG-encoded peptides by predicting their affinity to MHCs and excluded sequence identity to abundantly expressed proteins by interrogating the UniProt protein-database. The predicted affinity of selected peptides was validated in T2-cell peptide-binding assays in which many showed binding-kinetics like a very immunogenic influenza control peptide. Collectively, we provide an exquisitely curated catalogue of cancer-specific and highly MHC-affine peptides across 50 cancer types, and a freely available software (https://github.com/JSGerke/RAVENsoftware) to easily apply our algorithm to any gene expression dataset. We anticipate that our peptide libraries and software constitute a rich resource to advance anti-cancer immunotherapy.
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