Milea Timbergen

26 in exon 3”. The number of DTF patients assigned to this group decreases over time since next generation sequencing is able to detect ß-catenin mutations located on exon 3, in tumours where the traditional Sanger sequencing method is not sensitive enough 43, 44 . Interestingly, the β-catenin mutations observed in DTF are almost exclusively confined to residues T41 and S45, while alterations at other N-terminal phosphorylation residues, that is D32-S37, are rarely observed. Recently, Rebouissou et al. showed in liver cancers that the T41 and S45 mutants activate the pathway only weakly compared to others 45 . Apparently, this weak activation is ideal for DTF outgrowth in line with the “just-right” signalling hypothesis that postulates that each tumour type selects for an optimal level of β-catenin signalling that is ideal for tumour initiation and progression 46 . In accordance, the APC mutant proteins observed in DTF retain some functionality in regulating β-catenin levels. The specific β-catenin mutation may be of clinical relevance since several groups reported a higher recurrence rate in CTNNB1 S45F mutated DTF tumours compared to other CTNNB1 (T41A) mutated tumours and WT DTF 30, 47-49 . This issue is however still under debate as others have reported contradictory results 41, 50 . Using a β-catenin reporter assay in primary DTF cultures, Tejpar et al. validated the enhanced β-catenin signalling present in DTF. They also showed that in the nucleus, β-catenin is mainly associated with TCF7L1 (also known as TCF3) to regulate target genes. Expression of TCF7 (TCF1) and LEF1 could not be identified, while solely a minority of DTF samples expressed TCF7L2 (TCF4) 51 . Others found that several matrix metalloproteinases (MMP-3, MMP-7 and MMP-9) are expressed in DTF implying a role for MMP’s in DTF invasiveness 52, 53 . In fact, Kong et al. showed that MMP inhibition decreases tumour invasion and motility 52 . Matono et al. showed that MMP7 is more abundantly expressed in CTNNB1 mutated DTF compared to CTNNB1 WT, and hypothesized a correlation between MMP7 and prognosis as previously was demonstrated in pancreatic cancer 54, 55 . The MMP- inhibitor ilomastat (galardin /GM6001) was investigated in two studies, showing a decrease in DTF-cell (human and murine) migration and invasion capability 52, 53 . In Apc +/ Apc 1638N mutant mice, DTF tumour volume was decreased (Table 1) 52 . 2