Journal Article
. 2019 Aug;572(7770).
doi: 10.1038/s41586-019-1450-6.

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
  • 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.

Understanding the Origin and Diversity of Macrophages to Tailor Their Targeting in Solid Cancers.
Karoline Kielbassa, Serena Vegna, Christel Ramirez, Leila Akkari.
Front Immunol, 2019 Oct 16; 10. PMID: 31611871    Free PMC article.
Review.
Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling.
Rachel Eyre, Denis G Alférez, +15 authors, Robert B Clarke.
Nat Commun, 2019 Nov 05; 10(1). PMID: 31676788    Free PMC article.
Cancer-Specific Loss of p53 Leads to a Modulation of Myeloid and T Cell Responses.
Julianna Blagih, Fabio Zani, +13 authors, Karen H Vousden.
Cell Rep, 2020 Jan 16; 30(2). PMID: 31940491    Free PMC article.
P53 versus inflammation: an update.
Khadeja-Tul Kubra, Mohammad S Akhter, Mohammad A Uddin, Nektarios Barabutis.
Cell cycle (Georgetown, Tex.), 2019 Dec 28; 19(2). PMID: 31880200    Free PMC article.
Aberrant WNT/CTNNB1 Signaling as a Therapeutic Target in Human Breast Cancer: Weighing the Evidence.
Emma H van Schie, Renée van Amerongen.
Front Cell Dev Biol, 2020 Feb 23; 8. PMID: 32083079    Free PMC article.
Review.
Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms.
Ik Sun Kim, Yang Gao, +26 authors, Xiang H-F Zhang.
Nat Cell Biol, 2019 Aug 28; 21(9). PMID: 31451770    Free PMC article.
Highly Cited.
An Overview of Advances in Cell-Based Cancer Immunotherapies Based on the Multiple Immune-Cancer Cell Interactions.
Jialing Zhang, Stephan S Späth, Sherman M Weissman, Samuel G Katz.
Methods Mol Biol, 2019 Nov 30; 2097. PMID: 31776925    Free PMC article.
Inhibition of Wnt/β-Catenin Signaling in Neuroendocrine Tumors in vitro: Antitumoral Effects.
Xi-Feng Jin, Gerald Spoettl, +2 authors, Christoph Josef Auernhammer.
Cancers (Basel), 2020 Feb 09; 12(2). PMID: 32033025    Free PMC article.
p53's Extended Reach: The Mutant p53 Secretome.
Evangelos Pavlakis, Thorsten Stiewe.
Biomolecules, 2020 Feb 23; 10(2). PMID: 32075247    Free PMC article.
Review.

;. PMID: 32195007
Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments.
Ugo Testa, Germana Castelli, Elvira Pelosi.
Med Sci (Basel), 2020 Mar 27; 8(1). PMID: 32210163    Free PMC article.
Review.
CIMT 2019: report on the 17th Annual Meeting of the Association for Cancer Immunotherapy.
Jan David Beck, Matthias Birtel, +5 authors, Mustafa Diken.
Hum Vaccin Immunother, 2019 Oct 05; 16(4). PMID: 31584850    Free PMC article.
Influence of Innate Immunity on Cancer Cell Stemness.
Anna Pastò, Francesca Maria Consonni, Antonio Sica.
Int J Mol Sci, 2020 May 14; 21(9). PMID: 32397392    Free PMC article.
Review.
P53: A Guardian of Immunity Becomes Its Saboteur through Mutation.
Arjelle Decasa Agupitan, Paul Neeson, +3 authors, Ygal Haupt.
Int J Mol Sci, 2020 May 18; 21(10). PMID: 32414156    Free PMC article.
Review.
Mutant p53 as an Antigen in Cancer Immunotherapy.
Navid Sobhani, Alberto D'Angelo, +3 authors, Yong Li.
Int J Mol Sci, 2020 Jun 12; 21(11). PMID: 32521648    Free PMC article.
Review.
Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis.
Josef Leibold, Marcus Ruscetti, +22 authors, Scott W Lowe.
Cancer Discov, 2020 May 08; 10(7). PMID: 32376773    Free PMC article.
Molecular principles of metastasis: a hallmark of cancer revisited.
Jawad Fares, Mohamad Y Fares, +2 authors, Youssef Fares.
Signal Transduct Target Ther, 2020 Apr 17; 5(1). PMID: 32296047    Free PMC article.
Review.
Pro-inflammatory TNF-α and IFN-γ Promote Tumor Growth and Metastasis via Induction of MACC1.
Dennis Kobelt, Chenyu Zhang, +4 authors, Ulrike Stein.
Front Immunol, 2020 Jul 17; 11. PMID: 32670264    Free PMC article.
MDMX inhibits casein kinase 1α activity and stimulates Wnt signaling.
Qingling Huang, Lihong Chen, Ernst Schonbrunn, Jiandong Chen.
EMBO J, 2020 Jun 09; 39(14). PMID: 32511789    Free PMC article.
The expanding landscape of inflammatory cells affecting cancer therapy.
Ralph Weissleder, Mikael J Pittet.
Nat Biomed Eng, 2020 Mar 24; 4(5). PMID: 32203281    Free PMC article.
Review.
Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer.
Darrell Green, Heather Eyre, +18 authors, Katherine G Finegan.
Oncogene, 2020 Jul 14; 39(33). PMID: 32655131    Free PMC article.
Interleukin-1β and Cancer.
Cédric Rébé, François Ghiringhelli.
Cancers (Basel), 2020 Jul 09; 12(7). PMID: 32635472    Free PMC article.
Review.
Neutrophils: Orchestrators of the Malignant Phenotype.
Brian E Hsu, Yunyun Shen, Peter M Siegel.
Front Immunol, 2020 Aug 28; 11. PMID: 32849639    Free PMC article.
Review.
P53 in the impaired lungs.
Mohammad A Uddin, Nektarios Barabutis.
DNA Repair (Amst), 2020 Aug 28; 95. PMID: 32846356    Free PMC article.
Review.
Dietary Flavonoids in p53-Mediated Immune Dysfunctions Linking to Cancer Prevention.
Shoib Sarwar Siddiqui, Sofia Rahman, H P Vasantha Rupasinghe, Cijo George Vazhappilly.
Biomedicines, 2020 Aug 23; 8(8). PMID: 32823757    Free PMC article.
Review.
Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.
Shen Li, Yan Xu, +5 authors, Xiangyu Ma.
NPJ Precis Oncol, 2020 Sep 15; 4. PMID: 32923685    Free PMC article.
The complexity of neutrophils in health and disease: Focus on cancer.
Silvia Carnevale, Somayehsadat Ghasemi, Anna Rigatelli, Sebastien Jaillon.
Semin Immunol, 2020 Sep 23;. PMID: 32958359    Free PMC article.
Review.
Tumor-Promoting Ly-6G+ SiglecFhigh Cells Are Mature and Long-Lived Neutrophils.
Christina Pfirschke, Camilla Engblom, +11 authors, Mikael J Pittet.
Cell Rep, 2020 Sep 24; 32(12). PMID: 32966785    Free PMC article.
Systemic Reprogramming of Monocytes in Cancer.
Máté Kiss, Aarushi Audhut Caro, Geert Raes, Damya Laoui.
Front Oncol, 2020 Oct 13; 10. PMID: 33042791    Free PMC article.
Review.
COVID-19-Induced Modifications in the Tumor Microenvironment: Do They Affect Cancer Reawakening and Metastatic Relapse?
Federica Francescangeli, Maria Laura De Angelis, +3 authors, Ann Zeuner.
Front Oncol, 2020 Nov 17; 10. PMID: 33194755    Free PMC article.
CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress.
Ozlen Balcioglu, Richard E Heinz, +11 authors, Benjamin T Spike.
Breast Cancer Res, 2020 Nov 15; 22(1). PMID: 33187540    Free PMC article.
Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities.
Xiufang Xu, Miaofeng Zhang, Faying Xu, Shaojie Jiang.
Mol Cancer, 2020 Nov 26; 19(1). PMID: 33234169    Free PMC article.
Review.
Metastatic Colonization: Escaping Immune Surveillance.
Julien Schaller, Judith Agudo.
Cancers (Basel), 2020 Nov 20; 12(11). PMID: 33207601    Free PMC article.
Review.
CircCNTNAP3-TP53-positive feedback loop suppresses malignant progression of esophageal squamous cell carcinoma.
Hui Wang, Xuming Song, +6 authors, Gaochao Dong.
Cell Death Dis, 2020 Nov 27; 11(11). PMID: 33239613    Free PMC article.