Spatial genomic, biochemical and cellular mechanisms underlying meningioma heterogeneity and evolution

Calixto-Hope G Lucas; Kanish Mirchia; Kyounghee Seo; Hinda Najem; William C Chen; Naomi Zakimi; Kyla Foster; Charlotte D Eaton; Martha A Cady; Abrar Choudhury; S John Liu; Joanna J Phillips; Stephen T Magill; Craig M Horbinski; David A Solomon; Arie Perry; Harish N Vasudevan; Amy B Heimberger; David R Raleigh

doi:10.1038/s41588-024-01747-1

Spatial genomic, biochemical and cellular mechanisms underlying meningioma heterogeneity and evolution

Nat Genet. 2024 May 17. doi: 10.1038/s41588-024-01747-1. Online ahead of print.

Authors

Calixto-Hope G Lucas^{1

2

3}, Kanish Mirchia^#^{4

5

6}, Kyounghee Seo^#^{4

5

6}, Hinda Najem⁷, William C Chen^{4

5

6}, Naomi Zakimi^{4

5

6}, Kyla Foster^{4

5

6}, Charlotte D Eaton^{4

5

6}, Martha A Cady^{4

5

6}, Abrar Choudhury^{4

5

6}, S John Liu^{4

5

6}, Joanna J Phillips^{5

6}, Stephen T Magill⁷, Craig M Horbinski^{7

8}, David A Solomon⁶, Arie Perry^{5

6}, Harish N Vasudevan^{4

5}, Amy B Heimberger⁷, David R Raleigh^{9

10

11}

Affiliations

¹ Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
² Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Neurological Surgery, Northwestern University, Chicago, IL, USA.
⁸ Department of Pathology, Northwestern University, Chicago, IL, USA.
⁹ Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA. david.raleigh@ucsf.edu.
¹⁰ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. david.raleigh@ucsf.edu.
¹¹ Department of Pathology, University of California San Francisco, San Francisco, CA, USA. david.raleigh@ucsf.edu.

^# Contributed equally.

PMID: 38760638
DOI: 10.1038/s41588-024-01747-1

Abstract

Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spatial approaches to identify genomic, biochemical and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal and spatial evolution of high-grade meningiomas. We show that divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of subclonal copy number variants associated with treatment resistance. Multiplexed sequential immunofluorescence and deconvolution of meningioma spatial transcriptomes using cell types from single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K-AKT signaling and increased cell proliferation, which are associated with meningioma recurrence. To translate these findings to preclinical models, we use CRISPR interference and lineage tracing approaches to identify combination therapies that target intratumor heterogeneity in meningioma cell co-cultures.