Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology

Samuel V. Rasmussen; Jia Xiang Jin; Lissett R. Bickford; Andrew D. Woods; Felix Sahm; Kenneth A. Crawford; Kiyo Nagamori; Hiroaki Goto; Keila E. Torres; Angelo Sidoni; Erin R. Rudzinski; Khin Thway; Robin L. Jones; Alessio Ciulli; Hollis Wright; Melvin Lathara; Ganapati Srinivasa; Kavya Kannan; Paul H. Huang; Thomas G. P. Grünewald; Noah E. Berlow; Charles Keller

doi:10.1002/ctm2.961

Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology

Samuel V. Rasmussen, Jia Xiang Jin, Lissett R. Bickford, Andrew D. Woods, Felix Sahm, Kenneth A. Crawford, Kiyo Nagamori, Hiroaki Goto, Keila E. Torres, Angelo Sidoni, Erin R. Rudzinski, Khin Thway, Robin L. Jones (Lead / Corresponding author), Alessio Ciulli, Hollis Wright, Melvin Lathara, Ganapati Srinivasa, Kavya Kannan, Paul H. Huang (Lead / Corresponding author), Thomas G. P. Grünewald (Lead / Corresponding author)Noah E. Berlow, Charles Keller (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

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Abstract

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.

Original language	English
Article number	e961
Number of pages	22
Journal	Clinical and translational medicine
Volume	12
Issue number	7
Early online date	15 Jul 2022
DOIs	https://doi.org/10.1002/ctm2.961
Publication status	Published - Jul 2022

Keywords

Adolescent
Child
Chromosomal Proteins, Non-Histone/genetics
DNA-Binding Proteins/genetics
Genomics
Humans
Sarcoma/drug therapy
Transcription Factors/genetics
Young Adult

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Rasmussen, S. V., Jin, J. X., Bickford, L. R., Woods, A. D., Sahm, F., Crawford, K. A., Nagamori, K., Goto, H., Torres, K. E., Sidoni, A., Rudzinski, E. R., Thway, K., Jones, R. L., Ciulli, A., Wright, H., Lathara, M., Srinivasa, G., Kannan, K., Huang, P. H., ... Keller, C. (2022). Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology. Clinical and translational medicine, 12(7), Article e961. https://doi.org/10.1002/ctm2.961

@article{3200f288284d487c9ae30c9fa2a5c66b,

title = "Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology",

abstract = "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.",

keywords = "Adolescent, Child, Chromosomal Proteins, Non-Histone/genetics, DNA-Binding Proteins/genetics, Genomics, Humans, Sarcoma/drug therapy, Transcription Factors/genetics, Young Adult",

author = "Rasmussen, {Samuel V.} and Jin, {Jia Xiang} and Bickford, {Lissett R.} and Woods, {Andrew D.} and Felix Sahm and Crawford, {Kenneth A.} and Kiyo Nagamori and Hiroaki Goto and Torres, {Keila E.} and Angelo Sidoni and Rudzinski, {Erin R.} and Khin Thway and Jones, {Robin L.} and Alessio Ciulli and Hollis Wright and Melvin Lathara and Ganapati Srinivasa and Kavya Kannan and Huang, {Paul H.} and Gr{\"u}newald, {Thomas G. P.} and Berlow, {Noah E.} and Charles Keller",

note = "Copyright: {\textcopyright} 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.",

year = "2022",

month = jul,

doi = "10.1002/ctm2.961",

language = "English",

volume = "12",

number = "7",

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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 2022, 'Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology', Clinical and translational medicine, vol. 12, no. 7, e961. https://doi.org/10.1002/ctm2.961

TY - JOUR

T1 - Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology

AU - Rasmussen, Samuel V.

AU - Jin, Jia Xiang

AU - Bickford, Lissett R.

AU - Woods, Andrew D.

AU - Sahm, Felix

AU - Crawford, Kenneth A.

AU - Nagamori, Kiyo

AU - Goto, Hiroaki

AU - Torres, Keila E.

AU - Sidoni, Angelo

AU - Rudzinski, Erin R.

AU - Thway, Khin

AU - Jones, Robin L.

AU - Ciulli, Alessio

AU - Wright, Hollis

AU - Lathara, Melvin

AU - Srinivasa, Ganapati

AU - Kannan, Kavya

AU - Huang, Paul H.

AU - Grünewald, Thomas G. P.

AU - Berlow, Noah E.

AU - Keller, Charles

PY - 2022/7

Y1 - 2022/7

N2 - 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.

AB - 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.

KW - Adolescent

KW - Child

KW - Chromosomal Proteins, Non-Histone/genetics

KW - DNA-Binding Proteins/genetics

KW - Genomics

KW - Humans

KW - Sarcoma/drug therapy

KW - Transcription Factors/genetics

KW - Young Adult

U2 - 10.1002/ctm2.961

DO - 10.1002/ctm2.961

M3 - Article

C2 - 35839307

SN - 2001-1326

VL - 12

JO - Clinical and translational medicine

JF - Clinical and translational medicine

IS - 7

M1 - e961

ER -

Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology

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Keywords

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