EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model

Margit Bleijs, Corine Pleijte, Sem Engels, Femke Ringnalda, Friederike Meyer-Wentrup, Marc van de Wetering, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.

Original languageEnglish
JournalCancers
Volume13
Issue number23
DOIs
Publication statusPublished - 02 Dec 2021

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