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Transcriptome analysis reveals a role for the endothelial ANP-GC-A signaling in interfering with pre-metastatic niche
Takashi Nojiri1,2, Miki Arai3,4, Yutaka Suzuki4
1Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan.
Abstract:
Cancer establishes a microenvironment called the pre-metastatic niche in distant organs where disseminated cancer cells can efficiently metastasize. Pre-metastatic niche formation requires various genetic factors. Previous studies suggest that inhibiting a single niche-factor is insufficient to completely block pre-metastatic niche formation especially in human patients. Here we show that the atrial natriuretic peptide (ANP), an endogenous hormone produced by the heart, inhibits pre-metastatic niche formation and metastasis of murine solid cancer models when pharmacologically supplied in vivo. On the basis of a wealth of comprehensive RNA-seq data, we demonstrated that ANP globally suppressed expression of cancer-induced genes including known niche-factors in the lung. The lungs of mice overexpressing GC-A, a receptor for ANP in endothelial cells, were conferred resistance against pre-metastatic niche formation. Importantly, neither ANP administration nor GC-A overexpression had a detrimental effect on lung gene expression in a cancer-free condition. The current study establishes endothelial ANP-GC-A signaling as a therapeutic target to control the pre-metastatic niche.
Insights
Atrial natriuretic peptide (ANP) inhibits cancer metastasis by suppressing pre-metastatic niche formation. This hormone targets endothelial ANP-GC-A signaling, offering a new therapeutic strategy without harming healthy lung tissue.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Cancer metastasis relies on pre-metastatic niches in distant organs.
- Targeting single niche factors is often insufficient to block metastasis.
- Endogenous hormones represent potential therapeutic agents.
Purpose of the Study:
- To investigate the role of atrial natriuretic peptide (ANP) in pre-metastatic niche formation.
- To determine if ANP can inhibit cancer metastasis.
- To identify the molecular mechanisms underlying ANP's effect on pre-metastatic niches.
Main Methods:
- Pharmacological administration of ANP in murine solid cancer models.
- Comprehensive RNA-sequencing (RNA-seq) to analyze gene expression in the lung.
- Genetic manipulation of GC-A receptor expression in endothelial cells.
Main Results:
- ANP administration inhibited pre-metastatic niche formation and metastasis in vivo.
- ANP globally suppressed cancer-induced gene expression, including known niche factors, in the lung.
- Overexpression of the ANP receptor GC-A in lung endothelial cells conferred resistance to pre-metastatic niche formation.
- ANP and GC-A manipulation did not negatively impact lung gene expression in cancer-free conditions.
Conclusions:
- Endothelial ANP-GC-A signaling is a critical regulator of pre-metastatic niche formation.
- Targeting the ANP-GC-A pathway presents a promising therapeutic strategy to control cancer metastasis.
- This approach offers a specific mechanism to inhibit metastasis without systemic toxicity.