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

Creator(s)

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 L. Fridley, Children's Mercy Kansas CityFollow
Inna Smalley

Document Type

Article

Publication Date

6-18-2024

Identifier

DOI: 10.1016/j.xcrm.2024.101606

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.

Journal Title

Cell Rep Med

Volume

5

Issue

6

First Page

101606

Last Page

101606

MeSH Keywords

Melanoma; Humans; Tumor Microenvironment; Meningeal Neoplasms; Stromal Cells; Animals; Cell Line, Tumor; Mice; Gene Expression Regulation, Neoplastic; Transcriptome; Gene Expression Profiling; Meninges; Drug Resistance, Neoplasm; Signal Transduction; Female

Keywords

CSF; MAPK therapy; brain; central nervous system metastasis; drug resistance; leptomeningeal disease; leptomeninges; melanoma; metastasis; pia

Comments

This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://doi.org/10.1016/j.xcrm.2024.101606

Recommended Citation

Alhaddad H, Ospina OE, Khaled ML, et al. Spatial transcriptomics analysis identifies a tumor-promoting function of the meningeal stroma in melanoma leptomeningeal disease. Cell Rep Med. 2024;5(6):101606. doi:10.1016/j.xcrm.2024.101606