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Researchers identified TRIM11 as an E3 ligase that regulates the abundance of the EWSR1::ATF1 fusion protein driving clear cell sarcoma, a rare and aggressive cancer. When TRIM11 is depleted, the fusion protein accumulates excessively in cell nuclei, triggering lethal metabolic dysfunction through overexpression of the enzyme PCK1, which causes harmful depletion of metabolic intermediates and impaired energy production. The study reveals that paradoxically increasing rather than blocking fusion protein activity creates a therapeutic vulnerability in these cancer cells.
Why it matters
This finding opens a new treatment strategy for clear cell sarcoma by targeting TRIM11 to cause toxic overactivation of the cancer-driving fusion protein, rather than attempting direct inhibition. High PCK1 expression may serve as a biomarker to identify patients with more aggressive disease and shorter survival, potentially guiding clinical decision-making.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Clear cell sarcoma (CCS) is an ultra-rare and aggressive soft tissue sarcoma driven by the EWSR1::ATF1 fusion oncoprotein. Currently, no effective and well-tolerated treatment options are available to CCS patients. Direct inhibition of fusion transcription factors is precluded by the absence of defined ligand-binding pockets, whereas their abundance is under the control of the ubiquitin-proteasome system (UPS), offering an alternative avenue for biology-guided treatment. Here we show the abundance of EWSR1::ATF1 is tightly regulated by the UPS, and that release of this constraint is lethal to CCS cells. A reporter-based CRISPR/Cas9 knockout screen of UPS components identified TRIM11 as an E3 ligase that regulates turnover of EWSR1::ATF1, which it recognises as a neosubstrate without altering wild-type EWSR1 or ATF1. Depletion of TRIM11 increased nuclear fusion protein abundance, amplified the fusion-driven transcriptional programs and reduced viability. Proteomic analysis identified the cataplerotic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1), a direct EWSR1::ATF1 target, as the key mediator of lethal effects of fusion hyperactivation. Extracellular flux analysis, isotope tracing and quantitative metabolomics revealed excessive cataplerotic carbon withdrawal and impaired oxidative phosphorylation as the underlying mechanism. In patient tumors, high PCK1 expression associated with metastatic transcriptome programs and disease presentation, as well as shorter survival. Taken together, we report that hyperactivation of EWSR1::ATF1 opens a metabolic vulnerability, establishing TRIM11 as an actionable dependency and PCK1 as a candidate prognostic biomarker in CCS.