Evidence map›Paper›PMID 40804185›Full record

ArticleThe EMBO journal2025

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis.

Rema Iyer, Anagha Deshpande, Aditi Pedgaonkar, Pramod Akula Bala, Taehee Kim, Gerard L Brien, Darren Finlay, Kristiina Vuori, Alice Soragni, Hiromi I Wetterstein and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The EMBO journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors.

Rema IyerCancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Anagha DeshpandeCancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Aditi PedgaonkarCancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Pramod Akula BalaComputational Biology Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Taehee KimDepartment of Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.ORCID http://orcid.org/0000-0003-3565-7961
Gerard L BrienCancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK.
Darren FinlayCancer Molecular Therapeutics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.ORCID http://orcid.org/0000-0002-8718-9453
Kristiina VuoriCancer Molecular Therapeutics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.ORCID http://orcid.org/0000-0002-5657-0681
Alice SoragniDepartment of Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.ORCID http://orcid.org/0000-0002-6634-2885
Hiromi I WettersteinDepartment of Pathology, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, CA, USA.
Rabi MuradComputational Biology Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Aniruddha J DeshpandeCancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. adeshpande@sbpdiscovery.org.ORCID http://orcid.org/0000-0002-5240-9356

Funding

Tumor Microenvironment and Cancer ImmunologyP30CA030199 · NCI · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI ELENA B PASQUALE · 1985 to 2026
$107.2M
Molecular Pathogenesis of AF10-Rearranged LeukemiasR01CA262746 · NCI · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI Aniruddha J. Deshpande · 2022 to 2026
$2.2M
αvβ3-induced epithelial cancer progression via macrophage recruitmentK01OD030513 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WETTERSTEN, HIROMI INOUE · 2021 to 2025
$647k
HHS | NIH | National Cancer Institute (NCI) CA262746NCI NIH HHS P30 CA030199NCI NIH HHS R01 CA262746NIH HHS K01 OD030513
6 · The paper itself

Abstract

Synovial sarcoma (SySa) is an aggressive soft tissue sarcoma with an urgent need to develop targeted therapies. Here, we exploited specific vulnerabilities created by transcriptional rewiring by the fusion protein SS18::SSX, the sole oncogenic driver in SySa. To uncover genes that are selectively essential for the fitness of SySa cells compared to other tumor cell lines, we mined  the Cancer-Dependency-Map data. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) constituted one of the strongest dependencies both in vitro and in vivo. TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability. Transcriptomic profiling showed that SUMO2 inhibition elicited a profound reversal of the gene expression program orchestrated by SS18::SSX fusion. Further, genetic depletion or SUMO2 inhibition reduced global expression levels and chromatin occupancy of the SS18::SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark facilitating SySa pathogenesis. Taken together, our study identifies SUMO2 as a novel, selective vulnerability in synovial sarcoma, suggesting new avenues for targeted treatment of soft tissue tumors.

Indexed as

Epigenesis, GeneticOncogene Proteins, FusionSarcoma, SynovialSmall Ubiquitin-Related Modifier ProteinsAnimalsCarcinogenesisCell Line, TumorGene Expression Regulation, NeoplasticHumansMiceUbiquitinationOncogene Proteins, FusionSmall Ubiquitin-Related Modifier ProteinsSUMO2 protein, humanSUMO2Synovial Sarcoma

Identifiers

PMID40804185
PMCPMC12436642

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.