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

Max D. Wellenstein, Seth B. Coffelt, Danique E. M. Duits, Martine H. van Miltenburg, Maarten Slagter, Iris de Rink, Linda Henneman, Sjors M. Kas, Stefan Prekovic, Cheei-Sing Hau, Kim Vrijland, Anne Paulien Drenth, Renske de Korte-Grimmerink, Eva Schut, Ingrid van der Heijden, Wilbert Zwart, Lodewyk F. A. Wessels, Ton N. Schumacher, Jos Jonkers () and Karin E. de Visser ()
Additional contact information
Max D. Wellenstein: Oncode Institute, Netherlands Cancer Institute
Seth B. Coffelt: Oncode Institute, Netherlands Cancer Institute
Danique E. M. Duits: Oncode Institute, Netherlands Cancer Institute
Martine H. van Miltenburg: Oncode Institute, Netherlands Cancer Institute
Maarten Slagter: Oncode Institute, Netherlands Cancer Institute
Iris de Rink: Netherlands Cancer Institute
Linda Henneman: Netherlands Cancer Institute
Sjors M. Kas: Oncode Institute, Netherlands Cancer Institute
Stefan Prekovic: Netherlands Cancer Institute
Cheei-Sing Hau: Oncode Institute, Netherlands Cancer Institute
Kim Vrijland: Oncode Institute, Netherlands Cancer Institute
Anne Paulien Drenth: Oncode Institute, Netherlands Cancer Institute
Renske de Korte-Grimmerink: Netherlands Cancer Institute
Eva Schut: Oncode Institute, Netherlands Cancer Institute
Ingrid van der Heijden: Oncode Institute, Netherlands Cancer Institute
Wilbert Zwart: Netherlands Cancer Institute
Lodewyk F. A. Wessels: Oncode Institute, Netherlands Cancer Institute
Ton N. Schumacher: Oncode Institute, Netherlands Cancer Institute
Jos Jonkers: Oncode Institute, Netherlands Cancer Institute
Karin E. de Visser: Oncode Institute, Netherlands Cancer Institute

Nature, 2019, vol. 572, issue 7770, 538-542

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1450-6 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:572:y:2019:i:7770:d:10.1038_s41586-019-1450-6

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1450-6

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().