Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis.

Nature
Max D WellensteinKarin E de Visser

Abstract

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1β, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1β and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that pote...Continue Reading

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Methods Mentioned

BETA
flow cytometry
PCR
immunoprecipitation
FCS
magnetically
activated
protein assay
transfection
ChIP

Software Mentioned

edgeR
Tophat2
R
Tophat
limma voom
GraphPad Prism
lmFit
limma
ImageJ
Ingenuity Pathway Analysis software ( QIAGEN )

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