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Cell Reports Medicine

Cell Reports Medicine

IF: 11.7
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Spatial transcriptomics analysis identifies a tumor-promoting function of the meningeal stroma in melanoma leptomeningeal disease

Published:18 June 2024 DOI: 10.1016/j.xcrm.2024.101606 PMID: 38866016
Hasan Alhaddad,?Oscar E Ospina,?Mariam Lotfy Khaled,?Yuan Ren,?Ethan Vallebuona,?Mohammad Baraa Boozo,?Peter A Forsyth,?Yolanda Pina,?Robert Macaulay,?Vincent Law,?Kenneth Y Tsai,?W Douglas Cress,?Brooke Fridley,?Inna Smalley

Abstract

Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and patient-matched extra-cranial metastases using spatial transcriptomics in a small number of clinical specimens (nine tissues from two patients) with extensive in?vitro and in?vivo validation. The spatial landscape of melanoma LMD is characterized by a lack of immune infiltration and instead exhibits a higher level of stromal involvement. The tumor-stroma interactions at the leptomeninges activate tumor-promoting signaling, mediated through upregulation of SERPINA3. The meningeal stroma is required for melanoma cells to survive in the cerebrospinal fluid (CSF) and promotes MAPK inhibitor resistance. Knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in tumor cell death and re-sensitization to MAPK-targeting therapy. Our data provide a spatial atlas of melanoma LMD, identify the tumor-promoting role of meningeal stroma, and demonstrate a mechanism for overcoming microenvironment-mediated drug resistance in LMD.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
Trametinib 871700-17-3 C26H23FIN5O4 381 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 381 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 381 suppliers $28.00-$4391.10
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