PDGFRβ is necessary and sufficient for mutant p53-driven metastasis in a pancreatic cancer model.

  • Major finding: PDGFRβ is necessary and sufficient for mutant p53-driven metastasis in a pancreatic cancer model.

  • Mechanism: Mutant p53 sequesters p73 away from repressive transcriptional complexes at the Pdgfrb promoter.

  • Impact: Multikinase inhibitors targeting PDGFRβ may be useful to prevent the metastasis of p53-mutant tumors.

TP53 mutations frequently occur in human cancer and can lead to dominant-negative inhibition of wild-type p53 protein. Approximately 75% of pancreatic ductal adenocarcinomas (PDAC) harbor TP53 missense mutations, suggesting that mutation of p53 may play a role in PDAC progression. Pancreatic mouse models driven by Kras and Trp53 mutation are more metastatic than models with Trp53 null alleles, but it remains unclear whether mutant p53 contributes to the metastatic phenotype. Weissmueller and colleagues utilized cells generated from a pancreatic mouse model driven by mutant Kras and Trp53R172H that lost the remaining wild-type Trp53 allele to show that shRNA-mediated depletion of mutant p53 inhibits cell motility, invasion, and in vivo metastatic potential. Among genes that were differentially regulated following mutant p53 suppression, platelet-derived growth receptor factor β (PDGFRB) expression was required for these metastatic phenotypes. Mutant p53-dependent regulation of PDGFRB expression was confirmed in human pancreatic cancer cells, and silencing of PDGFRβ, but not PDGFRα, inhibited Kras/Trp53R172H murine cell invasion. Mechanistically, mutant p53 was shown to enhance Pdgfrb expression by sequestering p73, a p53 family member, away from transcriptional repressors such as NF-YB. In support of a role for PDGFRβ in mutant p53-driven metastasis, PDGFRβ knockdown or chemical inhibition of PDGFRβ with the tyrosine kinase inhibitor crenolanib reduced Kras/Trp53R172H murine pancreatic cancer cell invasion in vitro, and long-term inhibition of PDGFRβ via imatinib treatment of KRAS/p53 mutant mice harboring preneoplastic pancreatic lesions significantly reduced the incidence of metastasis. In patients, PDGFRB expression was shown to increase with PDAC tumor grade and to correlate with poor prognosis and metastasis in pancreatic, colorectal, and ovarian cancers harboring a mutant p53 gene signature. Together, these results highlight the role of PDGFRβ in mutant p53-driven metastasis and suggest that PDGFRβ may represent a useful prognostic marker and potential therapeutic target in cancers expressing mutant p53.

Weissmueller S, Manchado E, Saborowski M, Morris JP 4th, Wagenblast E, Davis CA, et al. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling. Cell 2014;157:382–94.