Drug Resistance in Melanoma-Related Leptomeningeal Disease

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Researchers uncovered potential mechanisms driving drug resistance in patients with melanoma and leptomeningeal disease, according to a recent study published by Alhaddad et al in Cell Reports Medicine.


Leptomeningeal disease is a rare and often lethal complication experienced by about 5% to 8% of patients with melanoma. The disease occurs when cancer cells spread to the membranes covering the brain and spinal cord, known as the leptomeninges, leading to rapid deterioration and drug resistance.

“Understanding the unique environment of leptomeningeal metastasis in melanoma has been a major challenge,” stressed senior study author Inna Smalley, PhD, Assistant Member of the Department of Metabolism and Physiology and a member of the Donald A. Adam Melanoma and Skin Cancer Center of Excellence at the Moffitt Cancer Center.

Study Methods and Results

Researchers used spatial transcriptomics to analyze tissue specimens from patients with melanoma and leptomeningeal disease and compared them with metastases from other parts of the body in the same patients.

The researchers found that melanoma cells in the leptomeninges interacted significantly with stromal cells. Under healthy conditions, stromal cells are critical in maintaining the health and function of various tissues and organs in the body. In melanoma metastases to the leptomeninges, the interactions between these stromal cells and the tumor activated tumor-promoting signals.

The researchers discovered spatially driven signaling pathways associated with melanoma growth and drug resistance—particularly in regions where tumor and stromal cells interacted. They identified the protein SERPINA3 as a regulator of the tumor-stroma interactions and a potential therapeutic target.

Additionally, the researchers examined melanoma cells’ metabolic challenges in the cerebrospinal fluid, demonstrating that the meningeal stroma may be essential for melanoma cells’ survival, and underscoring the importance of the tumor-stroma interaction.


“Our findings demonstrate that the ‘normal’ stromal cells in the leptomeninges play a crucial role in supporting tumor growth and resistance to MAPK inhibitors, a common melanoma treatment,” emphasized Dr. Smalley. “Our data suggest that targeting the tumor-stroma interaction, particularly through inhibition of SERPINA3-mediated signaling, could represent a novel strategy to overcome drug resistance in melanoma leptomeningeal disease. By disrupting this critical interaction, we may be able to enhance the efficacy of existing therapies and improve patient outcomes,” she concluded.

Disclosure: The research in this study was supported by the Melanoma Research Alliance, the American Cancer Society, and the National Institutes of Health. For full disclosures of the study authors, visit

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