
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.013
vdae090.013
Final Category: Basic Science Leptomeningeal Disease
AcademicSubjects/MED00300
AcademicSubjects/MED00310
BSLM-02 SPATIAL TRANSCRIPTOMICS ANALYSIS IDENTIFIES A UNIQUE TUMOR-PROMOTING FUNCTION OF THE MENINGEAL STROMA IN MELANOMA LEPTOMENINGEAL DISEASE
Alhaddad Hasan Moffitt Cancer Center, Tampa/FL, USA

Ospina Oscar Moffitt Cancer Center, Tampa/FL, USA

Khaled Mariam Moffitt Cancer Center, Tampa/FL, USA
Cairo University, Cairo, Egypt

Ren Yuan Moffitt Cancer Center, Tampa/FL, USA

Vallebuona Ethan Moffitt Cancer Center, Tampa/FL, USA

Boozo Mohammad Baraa Moffitt Cancer Center, Tampa/FL, USA

Forsyth Peter Moffitt Cancer Center, Tampa/FL, USA

Pina Yolanda Moffitt Cancer Center, Tampa/FL, USA

Macaulay Robert Moffitt Cancer Center, Tampa/FL, USA

Law Vincent Moffitt Cancer Center, Tampa/FL, USA

Tsai Kenneth Moffitt Cancer Center, Tampa/FL, USA

Cress Douglass Moffitt Cancer Center, Tampa/FL, USA

Fridley Brooke Moffitt Cancer Center, Tampa/FL, USA
Children’s Mercy Hospital, Kansas City/MO, USA

Smalley Inna Moffitt Cancer Center, Tampa/FL, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i5i5
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. The inaccessible nature of the disease site and lack of understanding of the biology of this unique metastatic site are major barriers to developing efficacious therapies for patients with melanoma LMD. Here, we characterize the tumor microenvironment of the leptomeningeal tissues and patient-matched extra-cranial metastatic sites using spatial transcriptomics analyses in clinical specimens, with extensive in vitro and in vivo validation. We show the spatial landscape of melanoma LMD to be characterized by a lack of immune infiltration and instead exhibit a higher level of stromal involvement. We show that the tumor-stroma interactions at the leptomeninges activate pathways implicated in tumor-promoting signaling, mediated through upregulation of SERPINA3 at the tumor-stroma interface. Our functional experiments establish that the meningeal stroma is required for melanoma cells to survive in the CSF environment and that these interactions lead to a lack of MAPK inhibitor sensitivity in the tumor. We show that knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in re-sensitization of the tumor to MAPK-targeting therapy and tumor cell death in the leptomeningeal environment using in vitro and in vivo models. Our data provides a spatial atlas of melanoma LMD, identifies the tumor-promoting role of meningeal stroma, and demonstrates a mechanism for overcoming microenvironment-mediated drug resistance unique to this metastatic site.
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pmc
