A Mutation Supercharges Tumor-Suppressor

Cancer researchers have long hailed p53, a tumor-suppressor protein, for its ability to keep unruly cells from forming tumors. But for such a highly studied protein, p53 has hidden its tactics well.

Scientists have identified a “super-mutant” variant of the tumor suppressor protein p53, which boosts the transcription factor’s ability to prevent pancreatic cancer development in mice models. “It’s not to say that mice with the mutated version of p53 would never get cancer, but this experiment suggests that this particular mutant is really potent in limiting tumor development,” notes Stanford University School of Medicine’s Laura Attardi, Ph.D., professor of radiation oncology and of genetics, who led the research.

The studies, published in Cancer Cell (“A p53 Super-Tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer”) also identified a p53-mediated pathway that is directly involved in tumor suppression. Dr. Attardi and colleagues suggest that their findings could lead to new anticancer approaches based either on mimicking the super-tumor suppressor p53 mutant, or inhibiting the existing cancer target Yap in p53-deficient tumor types.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of just 8%, due in part to difficulties in detecting the disease early, but also because pancreatic cancer is highly refractory to treatment. The tumor suppressor protein p53 is mutated in about 75% of PDACs, but we don’t yet understood which p53-related molecular pathways are critical to cancer suppression or development. “…if you simply ask how cells with and without p53 are different, you’ll see that there are at least 1000 genes whose expression is affected by p53 status,” Attardi comments. “So, getting to the bottom of which of those many genes are critical to tumor suppression is not a trivial question.”

To try and answer this question, the Stanford team tested the effects of different p53 mutations in mouse models of pancreatic cancer. In most cases the effects of changing p53 activity are not positive. Lack of p53 activity increases susceptibility to cancer development, whereas excess p53 activity can cause developmental problems. So, it came as a surprise when the Stanford team found that one particular hyperactivating p53 mutant acted as a super-tumor suppressor that kept mice free from tumors for longer than animals carrying normal p53. Whereas about 40% of mice with wild-type p53 developed pancreatic cancer by the time they reached 400 days old, none of the mice with the super-mutant p53 developed cancer. “What’s incredible about this mutant is that it hit a sweet spot,” Attardi said. “Embryos can make it through development without any obvious effects, and then adult mice show greatly enhanced resistance to tumor growth.… It’s not to say that mice with the mutated version of p53 would never get cancer, but this experiment suggests that this particular mutant is really potent in limiting tumor development.”

The authors found that the super-tumor suppressor p53 variant, p53^53,54TAD2, harbors a mutation in the TAD2 transcriptional activation domain and hyperactivates a large number of p53 target genes. But they then needed to identify which of the 100 or so genes that were activated in mice carrying the super-mutant p53 were directly involved in tumor suppression. Genomic data and previous work in human tumors led the researchers to look more closely at one gene in particular, Ptpn14, which encodes a negative regulator of the known oncoprotein Yap. They found that, like p53, Ptpn14 is “necessary and sufficient for pancreatic cancer suppression,” the team writes. In effect, the mutant p53 hyperactivated Ptpn14, which suppressed Yap to stop cancer development.

Working with Christina Curtis, Ph.D., assistant professor of medicine and of genetics, and Jose Seoane, Ph.D., Attardi’s team then used human cancer genomics data to show that when p53 is mutated in human cancers, Yap activity increases, which allows the tumors to form. This indicates that either p53 or Ptpn14 activity can lead to tumor-promoting Yap activation.

“I think this p53-Ptpn14-Yap axis is a central mechanism,” Attardi said. “p53 affects a lot of tumor-suppression processes, so if it influences a central protein like Yap, which also controls a lot of cancer processes, it can have widespread effects on cell behavior.” The researchers acknowledge that the p53-Ptpn14-Yap pathway is unlikely to be the only mechanism involved. However, Attardi states, “Clearly, Yap is a very potent oncogene. And our study suggests that perhaps the focus should be on developing Yap inhibitors for tumors where p53 is gone—maybe it’s more critical in those cancers.” The researchers are now carrying out studies in different experimental models to see if the p53-Ptpn14-Yap pathway is specific to pancreatic tumor development, or if it might be relevant for cancers that form in different tissues.

The reported findings have multiple therapeutic implications, the team suggests. “It may be possible to develop either a chemopreventive agent or cancer therapeutic for wild-type p53-expressing cancers that would perturb the interaction of the TAD2 domain with interacting partners and mimic the P53^53,54 mutant to enhance tumor suppression in vivo.” The findings may also aid in the development of treatments that block Yap. “…our discovery that Yap is activated in p53-deficient tumors suggests it as a potential therapeutic target in the many cancers that carry p53 mutations,” they continue. “Many therapeutic strategies aimed at targeting Yap are being explored.” One of these is the photosensitizer verteporfin, which is in clinical development for treating locally advanced pancreatic cancer. “It will be worthwhile to evaluate the particular efficacy of such therapies in p53-deficient cancers,” the authors conclude. “Through such strategies, future studies will leverage our enhanced understanding of p53  tumors suppression pathways to develop improved approaches to cancer therapy.”