USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer

Michaela Reissland, Oliver Hartmann, Saskia Tauch, Jeroen Bugter, Cristian Prieto-Garcia, Clemens Schulte, Sinah Loebbert, Daniel Solvie, Eliya Bitman-Lotan, Ashwin Narain, Anne-Claire Jacomin, Christina Schuelein-Voelk, Carmina T. Fuss, Nikolett Pahor, Carsten Ade, Viktoria Buck, Michael Potente, Vivian Li, Gerti Beliu, Armin WiegeringT.N. Grossmann, Martin Eilers, Elmar Wolf, Hans Michael Maric, Mathias T. Rosenfeldt, Madelon Maurice, Ivan Dikic, Peter Gallant, Amir Orian (Oryan), Markus E. Diefenbacher

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number22
Pages (from-to)3645-3659
JournalOncogene
Volume43
Issue number50
DOIs
Publication statusPublished - 23 Oct 2024

Funding

MR is funded by the DKH MSNZ Wuerzburg, DFG-GRK 2243 and IZKF B335. OH is supported by the German Cancer Aid via grant 70112491 and 70114554. ME is supported by the TransOnc priority programme of the German Cancer Aid within grant 70112951 (ENABLE). AO and MED are funded by the German Israeli Foundation grant 1431 1431 and ICRF project grant to AO. AO, ID and MED are funded by the DIP-DFG grant DIP DI 931/18-1. ID and MED are funded by the DFG-TRR 387. Open Access funding enabled and organized by Projekt DEAL. HMM and CS are funded by the DFG (DFG MA6957/1-1). The Operetta High Content Microscope was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) -440766788 (INST 93/1023-1 -FUGG).

FundersFunder number
DFG-TRR
Israel Cancer Research Fund
Deutsche ForschungsgemeinschaftDFG MA6957/1-1, INST 93/1023-1 -FUGG
Deutsche Forschungsgemeinschaft
German Israeli Foundation1431 1431
DIP-DFGDIP DI 931/18-1
Deutsche Krebshilfe70112491, 70114554, 70112951
Deutsche Krebshilfe

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