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

Wellenstein, M. D. et al. (2019) Loss of p53 triggers Wnt-dependent systemic inflammation to drive breast cancer metastasis. Nature, 572, pp. 538-542. (doi: 10.1038/s41586-019-1450-6) (PMID:31367040) (PMCID:PMC6707815)

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 potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer.

• Item Type: Articles (Letter)
• Additional Information: Research in the De Visser laboratory is funded by a European Research Council Consolidator award (ERC InflaMet 615300), the Netherlands Organization for Scientific Research (NWO-VICI 91819616), Oncode Institute, the Dutch Cancer Society (KWF10083; KWF10623) and the Beug Foundation for Metastasis Research. K.E.d.V. is an EMBO Young Investigator. Research in the Jonkers laboratory is funded by ERC Synergy grant 319661.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Coffelt, Professor Seth
• Authors: Wellenstein, M. D., Coffelt, S. B., Duits, D. E.M., van Miltenburg, M. H., Slagter, M., de Rink, I., Henneman, L., Kas, S. M., Prekovic, S., Hau, C.-S., Vrijland, K., Drenth, A. P., de Korte-Grimmerink, R., Schut, E., van der Heijden, I., Zwart, W., Wessels, L. F.A., Schumacher, T. N.M., Jonkers, J., and de Visser, K. E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Nature
• Publisher: Nature Publishing Group
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 31 July 2019
• Copyright Holders: Copyright © Springer Nature, 2019
• First Published: First published in Nature 572:538-542
• Publisher Policy: Reproduced in accordance with the publisher copyright policy