Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis
Open accessAbstract
Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer 1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival 3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis 4,5. 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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Some missense mutant proteins can lose the transcriptional effects of wild-type genes, such as keeping PDL1 expression low, making cancer cells more susceptible to cytotoxic T cells and NK cells, limiting the immune system's ability to attack cancer cells.
“Some missense mutant proteins can lose the transcriptional effects of wild-type genes, such as keeping PDL1 expression levels low, thereby making cancer cells more susceptible to cytotoxic T cells and NK cells, limiting the immune system’s ability to attack cancer cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [614]
Activating wild-type proteins can increase IFNγ signaling and sensitize tumors to immune checkpoint inhibitors, whereas corresponding mutant proteins can reduce the efficacy of immune checkpoint inhibitors.
“On the other hand, activating wild-type proteins can increase IFNγ signaling and sensitize tumors to immune checkpoint inhibitors, whereas corresponding mutant proteins can reduce the efficacy of immune checkpoint inhibitors.612–614”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [614]
The status of genes can influence tumor cells through the impact of wild-type gene loss and through their effects on the tumor immune microenvironment.
“In brief, the status of genes can influence tumor cells not only through the impact of wild-type gene loss but also through their effects on the TIME.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [614]
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- 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., Jonkers, J., & de Visser, K. E.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Jonkers, Jos
- ORCID
- Venue
- Nature
- Published
- 2019-07-31
- Volume
- 572
- Issue
- 7770
- Pages
- 538-542
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6707815
- OpenAlex
- W2965576600
- Cited by
- 500
- References
- 48
- Citations by year
- 2026: 39 · 2025: 67 · 2024: 89 · 2023: 70 · 2022: 90 · 2021: 75 · 2020: 60 · 2019: 9
- FWCI
- 23.33
- Type
- journal article
- Language
- en
- Open access
- green
- eprints.gla.ac.uk
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Inflammatory Biomarkers in Disease Prognosis
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- p53 deficiency, breast cancer metastasis, Wnt signaling, systemic inflammation, neutrophilia, tumour-associated macrophages, IL-1β, tumor microenvironment, genetically engineered mouse models
- MeSH terms
- Animals, Breast Neoplasms, Disease Models, Animal, Female, Inflammation, Neoplasm Metastasis, Neutrophils, Tumor Suppressor Protein p53, Wnt Proteins, Mice, Interleukin-1beta
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