Spatially resolved transcriptomic profiles reveal unique defining molecular features of infiltrative 5ALA-metabolizing cells associated with glioblastoma recurrence
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Published:2023-07-11
Issue:1
Volume:15
Page:
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ISSN:1756-994X
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Container-title:Genome Medicine
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language:en
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Short-container-title:Genome Med
Author:
Andrieux Geoffroy, Das Tonmoy, Griffin Michaela, Straehle Jakob, Paine Simon M. L., Beck Jürgen, Boerries Melanie, Heiland Dieter H., Smith Stuart J., Rahman Ruman, Chakraborty SajibORCID
Abstract
Abstract
Background
Spatiotemporal heterogeneity originating from genomic and transcriptional variation was found to contribute to subtype switching in isocitrate dehydrogenase-1 wild-type glioblastoma (GBM) prior to and upon recurrence. Fluorescence-guided neurosurgical resection utilizing 5-aminolevulinic acid (5ALA) enables intraoperative visualization of infiltrative tumors outside the magnetic resonance imaging contrast-enhanced regions. The cell population and functional status of tumor responsible for enhancing 5ALA-metabolism to fluorescence-active PpIX remain elusive. The close spatial proximity of 5ALA-metabolizing (5ALA +) cells to residual disease remaining post-surgery renders 5ALA + biology an early a priori proxy of GBM recurrence, which is poorly understood.
Methods
We performed spatially resolved bulk RNA profiling (SPRP) analysis of unsorted Core, Rim, Invasive margin tissue, and FACS-isolated 5ALA + /5ALA − cells from the invasive margin across IDH-wt GBM patients (N = 10) coupled with histological, radiographic, and two-photon excitation fluorescence microscopic analyses. Deconvolution of SPRP followed by functional analyses was performed using CIBERSORTx and UCell enrichment algorithms, respectively. We further investigated the spatial architecture of 5ALA + enriched regions by analyzing spatial transcriptomics from an independent IDH-wt GBM cohort (N = 16). Lastly, we performed survival analysis using Cox Proportinal-Hazards model on large GBM cohorts.
Results
SPRP analysis integrated with single-cell and spatial transcriptomics uncovered that the GBM molecular subtype heterogeneity is likely to manifest regionally in a cell-type-specific manner. Infiltrative 5ALA + cell population(s) harboring transcriptionally concordant GBM and myeloid cells with mesenchymal subtype, -active wound response, and glycolytic metabolic signature, was shown to reside within the invasive margin spatially distinct from the tumor core. The spatial co-localization of the infiltrating MES GBM and myeloid cells within the 5ALA + region indicates PpIX fluorescence can effectively be utilized to resect the immune reactive zone beyond the tumor core. Finally, 5ALA + gene signatures were associated with poor survival and recurrence in GBM, signifying that the transition from primary to recurrent GBM is not discrete but rather a continuum whereby primary infiltrative 5ALA + remnant tumor cells more closely resemble the eventual recurrent GBM.
Conclusions
Elucidating the unique molecular and cellular features of the 5ALA + population within tumor invasive margin opens up unique possibilities to develop more effective treatments to delay or block GBM recurrence, and warrants commencement of such treatments as early as possible post-surgical resection of the primary neoplasm.
Funder
Brain Tumour Charity Deutsche Forschungsgemeinschaft Else Kröner-Fresenius-Stiftung Bundesministerium für Bildung und Forschung Universitätsklinikum Freiburg
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
Reference84 articles.
1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96. 2. Smith SJ, Diksin M, Chhaya S, Sairam S, Estevez-Cebrero MA, Rahman R. The invasive region of glioblastoma defined by 5ALA guided surgery has an altered cancer stem cell marker profile compared to central tumour. Int J Mol Sci. 2017;18(11):2452. 3. Lee JK, Wang J, Sa JK, Ladewig E, Lee HO, Lee IH, Kang HJ, Rosenbloom DS, Camara PG, Liu Z, et al. Spatiotemporal genomic architecture informs precision oncology in glioblastoma. Nat Genet. 2017;49:594–9. 4. Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, Curtis C, Watts C, Tavare S. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A. 2013;110:4009–14. 5. Lan X, Jorg DJ, Cavalli FMG, Richards LM, Nguyen LV, Vanner RJ, Guilhamon P, Lee L, Kushida MM, Pellacani D, et al. Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy. Nature. 2017;549:227–32.
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