The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis

Background:

• KRAS mutations are a major cause of poor survival in lung cancer patients with bone metastasis.
• Effective therapeutic strategies for lung cancer bone metastasis remain limited.

Purpose of the Study:

• To identify key molecular targets in pan-KRAS-mutant lung cancer bone metastasis.
• To investigate the role of homeobox C10 (HOXC10) in this disease context.
• To explore potential therapeutic strategies targeting HOXC10.

Main Methods:

• RNA sequencing (RNA-seq) and patient tissue analysis to assess HOXC10 expression.
• In vitro cell proliferation and migration assays.
• In vivo studies using bioluminescence imaging and micro-CT to evaluate bone metastasis.
• Mechanistic studies on the NOD1/ERK signaling pathway and epithelial-mesenchymal transition (EMT).

Main Results:

• HOXC10 expression is significantly upregulated in KRAS-mutant lung cancer bone metastasis.
• Genetic depletion of HOXC10 inhibits cancer cell proliferation and migration in vitro.
• HOXC10 inhibition reduces bone metastasis in vivo.
• HOXC10 activates the NOD1/ERK pathway, promoting EMT and altering the bone microenvironment.
• Combined HOXC10 inhibition and STAT3 inhibition trigger ferroptosis, showing efficacy against bone metastasis.

Conclusions:

• HOXC10 is a critical mediator in pan-KRAS-mutant lung cancer bone metastasis via the NOD1/ERK axis.
• Targeting HOXC10 offers a potential therapeutic avenue for this patient population.
• Combination therapy involving HOXC10 inhibition presents a promising strategy for treating lung cancer bone metastasis.