Comprehensive Multi-Omic Profiling of Desmoplastic Small Round Cell Tumors Identifies Targetable Pathways with Therapeutic Opportunities

作者：Jamie M. Keck, Limin Zhu, Jayne M. Stommel, Julian Egger, Tugba Y. Ozmen, Furkan Ozmen, Jinho Lee, Benjamin J. Tate, Matthew J. Rames, Allison Creason, Christopher G. Suciu, Joanna Pucilowska, Gordon Brent Mills, Lara Emily Davis · 发表于：Molecular Cancer Research · 年份：2026 · DOI：10.1158/1541-7786.mcr-25-1134 · 研究领域：Sarcoma Diagnosis and Treatment、Protein Degradation and Inhibitors、Glioma Diagnosis and Treatment

Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive, fusion-driven sarcomas with poor outcomes despite intensive chemotherapy. Utilization of targeted therapies in DSRCT remains limited, underscoring the need for deeper characterization of patient tumors. To address this, we performed multi-omic profiling on nine patient-derived tumor biopsies from five patients enrolled in a precision oncology program. We consistently observed elevated mRNA and protein expression of human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), and DNA damage response (DDR) markers, and characterized these molecular features using an integrated assay suite including bulk and single-cell RNA sequencing, protein profiling, immunohistochemistry, immune analyses, and functional homologous recombination deficiency (HRD) testing. We define a replication stress-associated DNA damage landscape and identify functional HRD in a subset of tumors lacking genomic HRD scar signatures. Single-cell analyses reveal intra- and intertumoral heterogeneity, while longitudinal sampling uncovers treatment-dependent shifts in expression and activity that may contribute to adaptive resistance. The immune microenvironment is characterized by dysfunctional T-cell states and sparse antigen-presenting cells. Collectively, these analyses delineate recurrent, biologically targetable features and patient-specific vulnerabilities, establishing a foundation for biomarker-guided therapeutic strategies...