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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Systemic inflammation, indicated by high neutrophil-to-lymphocyte ratios, correlates with poor cancer outcomes.
• Neutrophils play a causal role in cancer metastasis.
• Mechanisms underlying systemic neutrophilic inflammation heterogeneity in cancer remain unclear.

Purpose of the Study:

• To investigate the role of cancer-cell-intrinsic p53 in regulating systemic neutrophilic inflammation and metastasis in breast cancer.
• To elucidate the molecular mechanisms linking p53 status to pro-metastatic inflammation.

Main Methods:

• Utilized 16 genetically engineered mouse models of breast cancer.
• Analyzed the impact of p53 loss on WNT ligand secretion, macrophage activation (IL-1β production), and systemic neutrophilia.
• Employed pharmacological and genetic strategies to block WNT secretion in p53-null cancer cells.

Main Results:

• Loss of p53 in cancer cells induced WNT ligand secretion, stimulating tumor-associated macrophages to produce IL-1β.
• This process drove systemic inflammation and promoted metastasis.
• Blocking WNT secretion in p53-null cells reversed IL-1β production and neutrophilic inflammation, reducing metastasis.

Conclusions:

• Cancer-cell-intrinsic p53 is a key regulator of pro-metastatic neutrophils.
• A mechanistic link exists between p53 loss, WNT secretion, and systemic neutrophilia, which potentiates metastatic progression.
• Tumor genetic makeup influences pro-metastatic inflammation, suggesting personalized immune intervention strategies.