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

Max D Wellenstein ¹, Seth B Coffelt ¹, Danique E M Duits ¹, Martine H van Miltenburg ², Maarten Slagter ³, Iris de Rink ⁴, Linda Henneman ⁵, Sjors M Kas ², Stefan Prekovic ⁶, Cheei-Sing Hau ¹, Kim Vrijland ¹, Anne Paulien Drenth ², Renske de Korte-Grimmerink ⁵, Eva Schut ², Ingrid van der Heijden ², Wilbert Zwart ⁶, Lodewyk F A Wessels ⁷, Ton N Schumacher ³, Jos Jonkers ⁸, Karin E de Visser ⁹

Affiliations

¹ Division of Tumour Biology & Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
² Division of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
³ Division of Molecular Oncology & Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁴ Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁵ Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁶ Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁷ Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁸ Division of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands. j.jonkers@nki.nl.
⁹ Division of Tumour Biology & Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands. k.d.visser@nki.nl.

PMID: 31367040
34 citations

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.

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