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000294136 1001_ $$00000-0002-4704-9392$$aReissland, Michaela$$b0
000294136 245__ $$aUSP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer.
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000294136 500__ $$a#EA:A100# / 2024 Dec;43(50):3645-3659
000294136 520__ $$aThe 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.
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000294136 7001_ $$aHartmann, Oliver$$b1
000294136 7001_ $$0P:(DE-He78)f112986f685bcedfb852b4c86803bece$$aTauch, Saskia$$b2$$udkfz
000294136 7001_ $$00000-0001-9920-2937$$aBugter, Jeroen M$$b3
000294136 7001_ $$aPrieto-Garcia, Cristian$$b4
000294136 7001_ $$00000-0003-2362-3318$$aSchulte, Clemens$$b5
000294136 7001_ $$aLoebbert, Sinah$$b6
000294136 7001_ $$00000-0003-4529-667X$$aSolvie, Daniel$$b7
000294136 7001_ $$aBitman-Lotan, Eliya$$b8
000294136 7001_ $$00000-0001-5905-3527$$aNarain, Ashwin$$b9
000294136 7001_ $$00000-0001-8761-1514$$aJacomin, Anne-Claire$$b10
000294136 7001_ $$aSchuelein-Voelk, Christina$$b11
000294136 7001_ $$aFuss, Carmina T$$b12
000294136 7001_ $$aPahor, Nikolett$$b13
000294136 7001_ $$00000-0001-7226-1179$$aAde, Carsten$$b14
000294136 7001_ $$00000-0001-6123-1599$$aBuck, Viktoria$$b15
000294136 7001_ $$aPotente, Michael$$b16
000294136 7001_ $$00000-0003-2041-0085$$aLi, Vivian$$b17
000294136 7001_ $$aBeliu, Gerti$$b18
000294136 7001_ $$00000-0001-7777-0909$$aWiegering, Armin$$b19
000294136 7001_ $$aGrossmann, Tom$$b20
000294136 7001_ $$00000-0002-0376-6533$$aEilers, Martin$$b21
000294136 7001_ $$aWolf, Elmar$$b22
000294136 7001_ $$00000-0002-2719-4752$$aMaric, Hans$$b23
000294136 7001_ $$00000-0001-7650-8458$$aRosenfeldt, Mathias$$b24
000294136 7001_ $$00000-0001-6885-5361$$aMaurice, Madelon M$$b25
000294136 7001_ $$00000-0001-8156-9511$$aDikic, Ivan$$b26
000294136 7001_ $$aGallant, Peter$$b27
000294136 7001_ $$00000-0002-8521-1661$$aOrian, Amir$$b28
000294136 7001_ $$aDiefenbacher, Markus E$$b29
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