YBX3 overexpression in mesothelioma drives aberrant cell proliferation
Abstract Malignant pleural mesothelioma (MpM) is a lethal tumour closely linked to asbestos exposure and is a cancer of unmet clinical need with no known oncogenic drivers. Recent advancements in technologies to identify RNA-binding proteins (RBPs) has uncovered an emerging role for RBP-RNA interactions in cancer progression and we therefore assessed changes in the RBPome of patient-derived MpM cell lines. We identify over 350 RBPs showing altered RNA binding, with functions consistent with key cancer hallmarks, and discovered YBX3 as a potential oncoprotein driving cell proliferation in MpM. Mechanistically we show the impact of YBX3 on cell growth is achieved through its control of the expression of the amino acid transporter SLC7A5/LAT1, with increased amino acid uptake increasing protein synthesis rates. Notably, we show the inhibition of cell growth by YBX3 deletion is recapitulated by the clinically-relevant SLC7A5/LAT1 inhibitor JPH203. Finally, we demonstrate that JPH203 sensitizes MpM cells to radiotherapy, which could provide a promising therapeutic strategy for MpM.
Authors
- Anne E. Willis (ORCID: https://orcid.org/0000-0002-1470-8531)
- Mark R. Southwood (ORCID: https://orcid.org/0000-0002-3493-9599)
- Marion MacFarlane (ORCID: https://orcid.org/0000-0001-7886-1159)
- Catherine Ficken (ORCID: https://orcid.org/0000-0003-4764-210X)
- John P. C. Le Quesne (ORCID: https://orcid.org/0000-0003-3552-7446)
- Andrew Craxton (ORCID: https://orcid.org/0000-0002-5957-9251)
- Stephan Kamrad (ORCID: https://orcid.org/0000-0002-5957-4661)
- Angela Rubio (ORCID: https://orcid.org/0000-0002-2849-612X)
- David Fernández‐Antorán (ORCID: https://orcid.org/0000-0003-1608-570X)
- Catarina Franco (ORCID: https://orcid.org/0000-0002-4759-8244)
- Lajos Kalmar
- Gorettu Munoz
- Kiran R. Patil
- Ian Powley
- Rui Guan
- Robert F. Harvey
Institutions
- University of Cambridge (GB)
- The Gurdon Institute (GB)
- Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo (ES)
- Instituto de Investigación Sanitaria Aragón (ES)
- Cancer Research UK Scotland Institute (GB)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- MRC Toxicology Unit (GB)
- University of Glasgow (GB)
- Universidad de Sevilla (ES)
- Medical Research Council (GB)
- Universidad Pablo de Olavide (ES)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1038/s41419-026-09389-3
- Primary Topic
- Occupational and environmental lung diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Medical Research Council
- Medical Research Foundation