NOTUM as alternative therapeutic approach to prevent clonal fixation and mutant expansion in patients predisposed to colorectal cancer

NOTUM from Apc-mutant cells biases clonal competition to initiate cancer

Flanagan DJ et al. Nature. 2021 June

Colorectal tumorigenesis has been a major focus of cancer research for decades. In 1990, Fearon and Vogelstein hypothesized a specific sequence of mutations, now called Adenoma Carcinoma Sequence, occurring during intestinal cancer development.¹ Later studies confirmed that loss-of-function mutations of the tumor suppression gene APC are an early, if not initiating, event in this sequence.²Indeed, APC is a negative regulator of WNT signaling, known as a key regulator of intestinal stem cells’ (ISC) homeostasis, intestinal epithelial cells’ proliferation, differentiation and regeneration, basically of intestinal epithelium physiopathology.³

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Many labs have studied the early molecular and cellular mechanisms of colorectal cancer initiation, i.e. how Apc-mutant cells take over in the epithelium. It has been showed that Apc-mutant ISCs need to outcompete wild-type (WT) ISCs for an adenoma to develop. This phenomenon is called “fixation” and is possible thanks to the clonal advantage that Apc loss confers to mutated ISCs.⁴

Two recent papers published in Nature identified the secreted WNT deacylase Notum as a major effector of early stage mutation fixation, that is, intestinal cancer development.^5,6 In Flanagan et al., the authors showed that Notum-upregulated expression in Apc-mutant ISCs favors their maintenance through active inhibition of WNT signaling in neighboring WT ISCs.⁵ This paracrine effect induces WT ISC differentiation allowing Apc-mutant cells to “win” and fix the epithelium with mutant progeny.

Interestingly, different NOTUM inhibitors are currently under development for the treatment of osteoporosis and neurodegenerative disorders.⁷ These new data suggest that the inhibition of NOTUM could also represent an alternative therapeutic approach to prevent clonal fixation and mutant expansion in patients predisposed to colorectal cancer.

Of note, the authors of this study used a newly developed conditional Notum allele allowing more robust recombination at the targeted locus than an existing model. This new mouse line was generated by genOway, a designer and provider of multiple preclinical models in several research areas including oncology, immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.

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References:

1. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759-67.
2. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, Kinzler KW. APC mutations occur early during colorectal tumorigenesis. Nature. 1992 Sep 17;359(6392):235-7.
3. Clevers H, Loh KM, Nusse R. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 2014 Oct 3;346(6205):1248012.
4. Vermeulen L, Morrissey E, van der Heijden M, Nicholson AM, Sottoriva A, Buczacki S, Kemp R, Tavaré S, Winton DJ. Defining stem cell dynamics in models of intestinal tumor initiation. Science. 2013 Nov 22;342(6161):995-8.
5. Flanagan DJ, Pentinmikko N, Luopajärvi K, Willis NJ, Gilroy K, Raven AP, Mcgarry L, Englund JI, Webb AT, Scharaw S, Nasreddin N, Hodder MC, Ridgway RA, Minnee E, Sphyris N, Gilchrist E, Najumudeen AK, Romagnolo B, Perret C, Williams AC, Clevers H, Nummela P, Lähde M, Alitalo K, Hietakangas V, Hedley A, Clark W, Nixon C, Kirschner K, Jones EY, Ristimäki A, Leedham SJ, Fish PV, Vincent JP, Katajisto P, Sansom OJ. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature. 2021 Jun;594(7863):430-435.
6. van Neerven SM, de Groot NE, Nijman LE, Scicluna BP, van Driel MS, Lecca MC, Warmerdam DO, Kakkar V, Moreno LF, Vieira Braga FA, Sanches DR, Ramesh P, Ten Hoorn S, Aelvoet AS, van Boxel MF, Koens L, Krawczyk PM, Koster J, Dekker E, Medema JP, Winton DJ, Bijlsma MF, Morrissey E, Léveillé N, Vermeulen L. Apc-mutant cells act as supercompetitors in intestinal tumour initiation. Nature. 2021 Jun;594(7863):436-441.
7. Zhao Y, Jolly S, Benvegnu S, Jones EY, Fish PV. Small-molecule inhibitors of carboxylesterase Notum. Future Med Chem. 2021 Jun;13(11):1001-1015.