Igniting Metastasis: CCR1 Promotes Lung Cancer Dissemination Through an ERK/c-FOS-RhoGDIβ Axis

Background: Lung cancer is one of the common malignancies worldwide and is spotlighted due to high mortality. Evidence indicates that RhoGDIβ is a crucial driver of lung cancer metastasis. Therefore, this study aims to elucidate the upstream mechanisms underlying the role of RhoGDIβ in metastatic progression of lung cancer. Methods: Potential RhoGDIβ-interacting proteins were identified using bioinformatic approaches. Functional assays were performed in lung cancer cell lines to assess migration, invasion, and epithelial-mesenchymal transition (EMT) following C-C chemokine receptor type 1 (CCR1) overexpression, extracellular signal-regulated kinase (ERK) pathway inhibition, or Proto-Oncogene C-Fos (c-FOS) induction. Moreover, signaling activity and RhoGDIβ expression were evaluated by immunoblotting. Additionally, a lung metastasis mouse model was used to validate metastatic nodule formation and pathway activation <i>in vivo</i>. Results: CCR1 overexpression significantly enhanced the metastatic behaviors of lung cancer cells, including migration, invasion, and EMT, and increased lung nodule formation in mice (<i>p</i> < 0.05). CCR1 overexpression also activated the ERK pathway, elevated levels of phosphorylated ERK (p-ERK) and c-FOS, and suppressed RhoGDIβ expression both <i>in vitro</i> and <i>in vivo</i> (<i>p</i> < 0.05). These trends were abolished by treatment with an ERK pathway inhibitor. Importantly, c-FOS overexpression rescued the effect of ERK blockade on metastasis inhibitory and RhoGDIβ upregulation, confirming that c-FOS was a downstream factor of ERK (<i>p</i> < 0.05). <i>In vivo</i> experiments further substantiated that CCR1 promoted metastasis through ERK/c-FOS-mediated repression of RhoGDIβ (<i>p</i> < 0.05). Conclusion: Our study unveils a novel CCR1-ERK-c-FOS signaling axis that promotes lung cancer metastasis and is associated with RhoGDIβ. Intervening in this axis represents a promising strategy for the migration of lung cancer metastasis.