Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology.
Date
2022-07-01ICR Author
Author
Rasmussen, SV
Jin, JX
Bickford, LR
Woods, AD
Sahm, F
Crawford, KA
Nagamori, K
Goto, H
Torres, KE
Sidoni, A
Rudzinski, ER
Thway, K
Jones, RL
Ciulli, A
Wright, H
Lathara, M
Srinivasa, G
Kannan, K
Huang, PH
Grünewald, TGP
Berlow, NE
Keller, C
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat. METHODS: In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance. RESULTS: Other biologically inspired functional interrogations of EPS cultures using gene knockdown or chemical probes demonstrated only limited to modest efficacy in vitro. However, our molecular studies uncovered distinguishing features (including retained dysfunctional SMARCB1 expression and elevated GLI3, FYN and CXCL12 expression) of distal, paediatric/young adult-associated EPS versus proximal, adult-associated EPS. CONCLUSIONS: Overall results highlight the complexity of the disease and a limited chemical space for therapeutic advancement. However, subtle differences between the two EPS subtypes highlight the biological disparities between younger and older EPS patients and emphasise the need to approach the two subtypes as molecularly and clinically distinct diseases.
Collections
Subject
SMARCB1
distal
epithelioid sarcoma
functional genomics
proximal
Research team
Mol and Systems Oncology
Language
eng
Date accepted
2022-06-17
License start date
2022-07-01
Citation
Clinical and Translational Medicine, 2022, 12 (7), pp. e961 -
Publisher
JOHN WILEY & SONS LTD