A supersuppressor for pancreatic cancer

Mutation or loss of the transcription factor p53 is associated with many cancers, particularly pancreatic ductal adenocarcinoma (PDAC). Therapies that restore or mimic the signaling of wild-type p53 may inhibit tumor growth and progression. Mello et al. generated a “super tumor-suppressor” p53 mutant (see also Aylon and Oren). Mutating one of the transcriptional activation domains (TAD53,54) in p53 prevented tumor growth in mice genetically predisposed to develop KRAS-induced PDAC. Chromatin binding and gene expression analyses of mouse tissue revealed that the TAD53,54-mutant p53 enhanced the transcription of the gene encoding the phosphatase PTPN14. Previous reports identified antimetastatic roles for PTPN14 (the abundance of which increases with cell density) in various cancers by inducing the cytoplasmic sequestration (and inhibition) of the transcription cofactor YAP or by inhibiting the secretion of prometastatic factors. YAP is a critical factor in PDAC progression. Indeed, p53(TAD53,54)-induced PTPN14 mediated tumor suppression in PDAC cells by relocalizing YAP to the cytoplasm but not in a manner dependent on its phosphatase activity. Histological analysis of patient tissue indicated that the p53-PTPN14-YAP axis was a conserved tumor-suppressive mechanism in a human pancreatic cancer, suggesting that the development of therapeutics toward this axis may block YAP-driven disease progression in PDAC patients. Furthermore, unlike previous attempts at activating p53 through other mutations or regulatory targets, expression of the TAD53,54-mutant p53 did not have any apparent detrimental effects in the mice. Thus, these findings may bring us one step closer to p53-targeted cancer therapy.

1. S. S. Mello, 
2. L. J. Valente, 
3. N. Raj, 
4. J. A. Seoane, 
5. B. M. Flowers, 
6. J. McClendon, 
7. K. T. Bieging-Rolett, 
8. J. Lee, 
9. D.Ivanochko, 
10. M. M. Kozak, 
11. D. T. Chang, 
12. T. A. Longacre, 
13. A. C. Koong, 
14. C. H. Arrowsmith, 
15. S. K. Kim, 
16. H. Vogel, 
17. L. D.Wood, 
18. R. H. Hruban, 
19. C. Curtis, 
20. L. D. Attardi
, A p53 super-tumor suppressor reveals a tumor suppressive p53-Ptpn14-Yap axis in pancreatic cancer. Cancer Cell 32, 460–473.e6 (2017)