Stabilisation of β-Catenin-WNT signalling by USP10 in APC-truncated colorectal cancer drives cancer stemness and enables super-competitor signalling

Author:

Reissland Michaela1,Hartmann Oliver1,Tauch Saskia2,Prieto-Garcia Cristian3,Schulte Clemens4ORCID,Solvie Daniel4ORCID,Loebbert Sinah5,Jacomin Anne-Claire6ORCID,Pesic Marina7,Bugter Jeroen8ORCID,Schülein-Völk Christina9,Fuss Carmina10,Pahor Nikolett1,Ade Carsten4ORCID,Buck Viktoria11,Potente Michael12,Li Vivian13ORCID,Beliu Gerti14,Wiegering Armin15ORCID,Bitman-Lotan Eliya16,Grossmann Tom17,Rosenfeldt Mathias4ORCID,Eilers Martin4ORCID,Maric Hans18ORCID,Maurice Madelon19ORCID,Greten Florian20ORCID,Dikic Ivan21ORCID,Oryan Amir16,Gallant Peter4,Diefenbacher Markus22ORCID

Affiliation:

1. Protein Stability and Cancer Group, University of Wuerzburg, Department of Biochemistry and Molecular Biology, Wuerzburg, Germany

2. Division of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Protein Stability and Cancer Group, University of Wuerzburg, Depar

3. Molecular Signalling Group, Institute of Biochemistry II, Goethe University Frankfurt, Germany

4. University of Würzburg

5. Mildred Scheel Early Career Center, Wuerzburg, Germany

6. Goethe-Universität Frankfurt

7. Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt am Main, Germany.

8. Oncode Institute and UMC Utrecht

9. Theodor-Boveri Institute

10. Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany; Protein Stability and Cancer Group, University of Wuerzbu

11. Institute for Pathology, University of Wuerzburg, Germany

12. Angiogenesis & Metabolism Laboratory, Berlin Institute of Health at Charite, Universitaetsmedizin Berlin, Berlin Germany and Max Delbrueck Center for Molecular Medicine in the Helmholtz Association,

13. The Francis Crick Institute

14. Rudolf-Virchow-Center for Integrative and Translational Imaging, University of Wuerzburg, Wuerzburg, Germany.

15. University Hospital, University of Wuerzburg

16. Faculty of Medicine, TICC, Technion Haifa, Israel

17. Amsterdam Institute of Molecular and Life Sciences, Amsterdam, Netherlands

18. Rudolf Virchow Center, Center for Integrative and Translational Bioimaging, University of Wü

19. Oncode Institute Centre for Molecular Medicine University Medical Centre Utrecht

20. Institute for Tumor Biology and Experimental Therapy

21. Goethe University

22. Biocenter University Wuerzburg

Abstract

Abstract The contribution of deubiquitylating enzymes to β-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as an APC-truncation- specific enhancer of β-Catenin stability, potentiating WNT signalling and cancer stem cells and CRC. Mechanistically, interaction and in vitro binding studies, together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and requires the absence of full-length APC. Reduction of USP10 induces the expression of differentiation genes and opposes the APC-truncated phenotype in an intestinal hyperplasia model. Notably, loss of USP10 in CRISPR engineered intestinal organoids opposed the super competitor-signalling and reduced tumorigenic properties of APC-mutated CRC. Taken together, our findings reveal USP10s role in CRC cell identity, stemness and tumour growth by stabilising β-Catenin, leading to aberrant WNT signalling, and implicate USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.

Publisher

Research Square Platform LLC

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