Triggering cell death in metastatic melanoma may pave the way for new cancer treatments

Good news! Cancer is history (soon)!

"Metastatic melanoma cells that have spread to lymph nodes survive by relying on a protein called ferroptosis suppressor protein 1 (FSP1)—a surprising metabolic dependency that could open the door to a new class of cancer treatments ... The researchers say the study not only highlights the therapeutic potential of drugs that inhibit FSP1, but also offers new ways to understand cancer and its vulnerabilities.

Ferroptosis is a form of cell death driven by excessive lipid oxidation in cell membranes. When this occurs, the cell’s structural integrity collapses, leading to death. Cancer cells rely heavily on antioxidant proteins like FSP1 to prevent ferroptosis. ..."

From the abstract:

"Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers. However, which ferroptosis surveillance systems may offer a therapeutic window to leverage redox maladaptation in cancer remains unclear. In melanoma, glutathione peroxidase 4 (GPX4) impedes ferroptosis during haematogenous metastasis, but is dispensable during lymphatic metastasis.

Here, using a metastatic mouse melanoma model selected for lymph node metastasis, we show that lymph-node-derived metastatic cells exhibit markedly diminished expression of glutamate–cysteine ligase (GCLC) and reduced glutathione (GSH) levels relative to their parental counterparts.

This metabolic shift occurs within the hypoxic lymphatic niche. Under comparable low-oxygen conditions, GPX4 undergoes ubiquitination and proteasomal degradation.

In response, lymph node metastatic cells acquire increased reliance on ferroptosis suppressor protein 1 (FSP1), which is localized with perinuclear lysosomes.

These findings reveal that the reduced reliance on the GPX4 axis enables melanoma cells to shift toward FSP1 dependency.

Notably, intratumoural monotherapy with selective FSP1 inhibitors (viFSP1 and FSEN1) effectively suppresses melanoma growth in lymph nodes, but not in subcutaneous tumours, emphasizing a microenvironment-specific dependency on FSP1.

Thus, targeting FSP1 in the lymph nodes holds strong potential for blocking melanoma progression."

Triggering cell death in metastatic melanoma may pave the way for new cancer treatments | Harvard T.H. Chan School of Public Health "Study offers new ways to understand cancer and its vulnerabilities, and suggests that certain protein inhibitors could potentially be effective treatments for the disease"

Lymph node environment drives FSP1 targetability in metastasizing melanoma (open access)

Fig. 1: LN metastatic lines exhibit elevated FSP1 and reduced GCLC, GPX4 and ACSL4 expression.