Insights into cancer risk from a tuberous sclerosis complex zebrafish model

Tuberous sclerosis complex (TSC) is a rare genetic disorder associated with benign tumour formation. The disease is caused by loss-of-function mutations in either of the tumour suppressor genes TSC1 or TSC2. In normal cells, the proteins encoded by these genes collectively inhibit mTORC1 (mechanistic target of rapamycin complex I) signalling; when absent, mTORC1 signalling is increased. Paradoxically, in other disorders characterised by augmented mTORC1 signalling, overt malignancies are observed. Ess and colleagues exploited this difference to gain mechanistic insights into tumorigenesis. They established a zebrafish model of TSC that develops cancer, by generating tsc2;p53 compound mutants. Compared with p53 single mutants, tumorigenesis and angiogenesis were enhanced in tsc2;p53 zebrafish. Treatment with an mTORC1 inhibitor, rapamycin, inhibited tumour formation. This work provides in vivo evidence that cancer risk in p53-deficient individuals might be modulated by TSC1 or TSC2 mutations. Page 925