Alveolar soft-part sarcoma (ASPS) resembles a mesenchymal stromal progenitor: evidence from meta-analysis of transcriptomic data

Abstract

Alveolar soft-part sarcoma (ASPS) is an extremely rare malignancy characterized by the unbalanced translocation der(17)t(X;17)(p11;q25). This translocation generates a fusion protein, ASPL-TFE3, that drives pathogenesis through aberrant transcriptional activity. Although considerable progress has been made in identifying ASPS therapeutic vulnerabilities (e.g., MET inhibitors), basic research efforts are hampered by the lack of appropriate in vitro reagents with which to study the disease. In this report, previously unmined microarray data for the ASPS cell line, ASPS-1, was analyzed relative to the NCI sarcoma cell line panel. These data were combined with meta-analysis of pre-existing ASPS patient microarray and RNA-seq data to derive a platform-independent ASPS transcriptome. Results demonstrated that ASPS-1, in the context of the NCI sarcoma cell panel, had some similarities to normal mesenchymal cells and connective tissue sarcomas. The cell line was characterized by high relative expression of transcripts such asCRYAB,MT1G,GCSAML,andSV2B.Notably, ASPS-1 lacked mRNA expression of myogenesis-related factorsMYF5,MYF6,MYOD1,MYOG,PAX3,andPAX7.Furthermore, ASPS-1 had a predicted mRNA surfaceome resembling an undifferentiated mesenchymal stromal cell through expression ofGPNMB,CD9(TSPAN29),CD26(DPP4),CD49C(ITGA3),CD54(ICAM1),CD63(TSPAN30),CD68(SCARD1),CD130(IL6ST),CD146(MCAM),CD147(BSG),CD151(SFA-1),CD166(ALCAM),CD222(IGF2R),CD230(PRP),CD236(GPC),CD243(ABCB1), andCD325(CDHN). Subsequent re-analysis of ASPS patient data generated a consensus expression profile with considerable overlap between studies. In common with ASPS-1, elevated expression was noted forCTSK,DPP4,GPNMB,INHBE,LOXL4,PSG9,SLC20A1,STS,SULT1C2,SV2B,andUPP1. Transcripts over-expressed only in ASPS patient samples includedABCB5,CYP17A1,HIF1A,MDK,P4HB,PRL,andPSAP.These observations are consistent with that expected for a mesenchymal progenitor cell with adipogenic, osteogenic, or chondrogenic potential. In summary, the consensus data generated in this study highlight the unique and highly conserved nature of the ASPS transcriptome. Although the ability of the ASPL-TFE3 fusion to perturb mRNA expression must be acknowledged, the prevailing ASPS transcriptome resembles that of a mesenchymal stromal progenitor.