New research from the Moffitt Cancer Center may have uncovered new therapeutic targets for leptomeningeal metastasis (LMD) in melanoma, a severe complication affecting 5%-8% of melanoma patients.

Researchers for the analysis used spatial transcriptomics to analyze tissue samples from two melanoma patients, including five leptomeningeal and four extra-cranial metastases. The analysis revealed unique gene expression profiles and cellular compositions between the two sites. The leptomeningeal metastases showed lower immune infiltration and higher stromal involvement when compared with extra-cranial metastases.

Among the important study findings:

• The identification of complement and coagulation and TGF-β signaling pathways as significantly enriched in the setting leptomeningeal metastases.
• Fibroblast-like meningeal cells in the leptomeninges were shown to express genes promoting melanoma cell survival and drug resistance, including SERPINA3.
• This gene has been implicated in the activation of the PI3K/AKT and MAPK signaling pathways, contributing to resistance against MAPK-targeting therapies.

“Understanding the unique environment of leptomeningeal metastasis in melanoma has been a major challenge," said Inna Smalley, PhD, a senior author and assistant member of the Department of Metabolism and Physiology and a member of the Donald A. Adam Melanoma and Skin Cancer Center of Excellence, in a news release. "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.” 

The small sample size was cited as a study limitation.

"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,” Smalley added. “By disrupting this critical interaction, we may be able to enhance the efficacy of existing therapies and improve patient outcomes.”

Source: Alhaddad H, et al. Cell Reports Medicine. Doi:10.1016/j.xcrm.2024.101606