USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer
The contribution of deubiquitylating enzymes (DUBs) to β-Catenin stabilization in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, and by using an unbiassed screen, we discovered that the DUB USP10 stabilizes β-Catenin specifically in APC-truncated CRC in vitro and in vivo. Mechanistic studies, including in vitro binding together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and is outcompeted by intact APC, favouring β-catenin degradation. However, in APC-truncated cancer cells USP10 binds to β-catenin, increasing its stability which is critical for maintaining an undifferentiated tumour identity. Elimination of USP10 reduces the expression of WNT and stem cell signatures and induces the expression of differentiation genes. Remarkably, silencing of USP10 in murine and patient-derived CRC organoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype, reducing tumorigenic properties of APC-truncated CRC. These findings are clinically relevant as patient-derived organoids are highly dependent on USP10, and abundance of USP10 correlates with poorer prognosis of CRC patients. Our findings reveal, therefore, a role for USP10 in CRC cell identity, stemness, and tumorigenic growth by stabilising β-Catenin, leading to aberrant WNT signalling and degradation resistant tumours. Thus, USP10 emerges as a unique therapeutic target in APC truncated CRC.
Authors
- Saskia Tauch (ORCID: https://orcid.org/0009-0001-3168-2038)
- Carsten Patrick Ade (ORCID: https://orcid.org/0000-0001-7226-1179)
- Oliver Hartmann (ORCID: https://orcid.org/0000-0002-5663-645X)
- Daniel Solvie (ORCID: https://orcid.org/0000-0003-4529-667X)
- Vivian Li (ORCID: https://orcid.org/0000-0003-2041-0085)
- Michaela Reissland (ORCID: https://orcid.org/0000-0002-4704-9392)
- Peter Gallant (ORCID: https://orcid.org/0000-0002-8270-5738)
- Hans Michael Maric (ORCID: https://orcid.org/0000-0002-2719-4752)
- Carmina Teresa Fuß (ORCID: https://orcid.org/0000-0002-1466-5287)
- Jeroen M. Bugter (ORCID: https://orcid.org/0000-0001-9920-2937)
- Martin Eilers (ORCID: https://orcid.org/0000-0002-0376-6533)
- Madelon M. Maurice (ORCID: https://orcid.org/0000-0001-6885-5361)
- Eliya Bitman-Lotan (ORCID: https://orcid.org/0000-0001-9174-6382)
- Markus E. Diefenbacher (ORCID: https://orcid.org/0000-0002-7402-7949)
- Sinah Loebbert
- Anne‐Claire Jacomin (ORCID: https://orcid.org/0000-0001-8761-1514)
- Michael Potente (ORCID: https://orcid.org/0000-0002-5689-0036)
- Clemens Schulte (ORCID: https://orcid.org/0000-0003-2362-3318)
- Amir Orian (ORCID: https://orcid.org/0000-0002-8521-1661)
- Armin Wiegering (ORCID: https://orcid.org/0000-0001-7777-0909)
- Nikolett Pahor
- Viktoria Buck (ORCID: https://orcid.org/0000-0001-6123-1599)
- Ashwin Narain (ORCID: https://orcid.org/0000-0001-5905-3527)
- Tom N. Grossmann (ORCID: https://orcid.org/0000-0003-0179-4116)
- Cristian Prieto‐Garcia (ORCID: https://orcid.org/0000-0002-7576-1061)
- Elmar Wolf (ORCID: https://orcid.org/0000-0002-5299-6335)
- Gerti Beliu (ORCID: https://orcid.org/0000-0003-1862-7912)
- Mathias T. Rosenfeldt (ORCID: https://orcid.org/0000-0001-7650-8458)
- Ivan Đikić (ORCID: https://orcid.org/0000-0001-8156-9511)
- Christina Schuelein‐Voelk
Institutions
- Goethe University Frankfurt (DE)
- Technion – Israel Institute of Technology (IL)
- German Cancer Research Center (DE)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- University of Würzburg (DE)
- The Francis Crick Institute (GB)
- Helmholtz Zentrum München (DE)
- University Medical Center Utrecht (NL)
- Comprehensive Cancer Center Mainfranken (DE)
- Oncode Institute (NL)
- Helmholtz Institute for RNA-based Infection Research (DE)
- Universitätsklinikum Würzburg (DE)
- German Center for Lung Research (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Max Planck Institute for Molecular Genetics (DE)
- DKFZ-ZMBH Alliance (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Oncogene
- Published
- 2024-10-23
- DOI
- https://doi.org/10.1038/s41388-024-03141-x
- Citations
- 14
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 3.27
Funders
- Israel Cancer Research Fund
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe