Publications

@article{Andrieux2023-pw,

title = {Spatially resolved transcriptomic profiles reveal unique 

 defining molecular features of infiltrative 5ALA-metabolizing 

 cells associated with glioblastoma recurrence},

author = {Geoffroy Andrieux and Tonmoy Das and Michaela Griffin and Jakob Straehle and Simon M L Paine and J\"{u}rgen Beck and Melanie Boerries and Dieter H Heiland and Stuart J Smith and Ruman Rahman and Sajib Chakraborty},

year  = {2023},

date = {2023-07-01},

journal = {Genome Med.},

volume = {15},

number = {1},

pages = {48},

publisher = {Springer Science and Business Media LLC},

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 CIBEROSRTx 

 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.},

keywords = {5ALA, Glioblastoma, Glycolysis, Mesenchymal subtype, Myeloid, Recurrence, Spatial transcriptomics, Wound response},

pubstate = {published},

tppubtype = {article}

}