Lymph node environment drives FSP1 targetability in metastasizing melanoma

Area of Science:

• Oncology
• Cancer Metastasis
• Cellular Metabolism

Background:

• Ferroptosis is a key target for overcoming therapy-resistant and metastatic cancers.
• Glutathione peroxidase 4 (GPX4) inhibits ferroptosis in hematogenous metastasis but is not essential for lymphatic metastasis in melanoma.
• The specific ferroptosis surveillance systems that can be therapeutically leveraged in cancer remain largely unknown.

Purpose of the Study:

• To investigate the ferroptosis mechanisms and metabolic adaptations of melanoma cells during lymphatic metastasis.
• To identify potential therapeutic targets within the lymphatic metastatic niche.

Main Methods:

• Utilized a metastatic mouse melanoma model selected for lymph node metastasis.
• Analyzed gene expression, protein levels, and metabolite concentrations (glutathione) in metastatic cells.
• Investigated the role of GPX4 and FSP1 in ferroptosis regulation under hypoxic conditions.
• Assessed the efficacy of FSP1 inhibitors (viFSP1, FSEN1) in vivo.

Main Results:

• Melanoma cells in the lymphatic niche showed decreased glutamate-cysteine ligase (GCLC) and glutathione (GSH) levels.
• Hypoxia induced GPX4 ubiquitination and degradation, leading to increased reliance on FSP1.
• FSP1 inhibitors suppressed melanoma growth specifically in lymph node tumors, not subcutaneous tumors.
• This highlights a microenvironment-specific dependency on FSP1 in lymph node metastases.

Conclusions:

• Reduced GPX4 activity allows melanoma cells to depend on FSP1 for survival in the hypoxic lymphatic niche.
• Targeting FSP1 in lymph nodes presents a promising strategy for blocking melanoma progression.
• FSP1 inhibition demonstrates potential as a targeted therapy for lymph node-positive melanoma.