p53 Loss Can Promote Neutrophilia, Increased WNT Signaling, and Metastasis

Recent evidence suggests that canonical driver mutations affect the local immune composition of primary tumors. Using 16 genetically engineered mouse models (GEMM) representing most subtypes of human breast cancer, Wellenstein, Coffelt, and colleagues showed that the mice had increased levels of circulating neutrophils—a condition that promotes metastasis. There was a large amount of variability in the degree of neutrophilia among the GEMMs, with p53-mutant mice having more circulating neutrophils. p53 loss was correlated with increased serum levels of CCL2, IL1β, and G-CSF, and systemic inflammation was correlated with tumor p53 status. Mice with tumors lacking p53 had increased neutrophil expansion compared to mice with size-matched p53-proficient tumors, implying a causal relationship between p53 loss and cancer-induced systemic neutrophilic inflammation. In cultured bone marrow–derived macrophages, conditioned medium from p53-mutant cells induced Il1b mRNA expression to a greater extent than medium from matched p53-proficient controls, and data from The Cancer Genome Atlas revealed that human breast tumors with TP53 mutations had increased IL1B expression compared to tumors with wild-type TP53. In the GEMMs, there was an increase in WNT and β-catenin signaling in p53-null tumors, as indicated by upregulation of WNT-related genes and WNT ligands, downregulation of genes encoding negative regulators of WNT signaling, increased levels of WNT1 and WNT7A proteins, and increased expression of nonphosphorylated, active β-catenin. A similar effect was seen in TP53-mutant human tumors and p53-deficient cancer cell lines, which exhibited increased expression of WNT ligands. Depletion of Porcn mRNA or treatment with LGK974, an inhibitor of porcupine (a WNT-specific acetyltransferase responsible for regulating secretion of WNT ligands), reduced macrophages’ expression of Il1b in the p53-null cells. Porcupine blockade reduced pulmonary metastases in mice, as did lack of p53, and LGK974 treatment decreased metastasis only in mice with p53-null tumors. These findings demonstrate that p53 mutations drive WNT-dependent metastasis, potentially in association with neutrophila.

Wellenstein MD, Coffelt SB, Duits DEM, van Miltenburg MH, Slagter M, de Rink I, et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature 2019 Jul 31 [Epub ahead of print].

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