Peer Review #2 of "Alveolar soft-part sarcoma (ASPS) resembles a mesenchymal stromal progenitor: evidence from meta-analysis of transcriptomic data (v0.2)"

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 as CRYAB, MT1G, GCSAML, and SV2B. Notably, ASPS-1 lacked mRNA expression of myogenesisrelated factors MYF5, MYF6, MYOD1, MYOG, PAX3, and PAX7. Furthermore, ASPS-1 had a predicted mRNA surfaceome resembling an undifferentiated mesenchymal stromal cell through expression of GPNMB, 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), and CD325 (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 for CTSK,