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@ARTICLE{Andrieux:277461,
      author       = {G. Andrieux and T. Das and M. Griffin and J. Straehle and
                      S. M. L. Paine and J. Beck and M. Börries$^*$ and D. H.
                      Heiland$^*$ and S. J. Smith and R. Rahman and S.
                      Chakraborty},
      title        = {{S}patially resolved transcriptomic profiles reveal unique
                      defining molecular features of infiltrative
                      5{ALA}-metabolizing cells associated with glioblastoma
                      recurrence.},
      journal      = {Genome medicine},
      volume       = {15},
      number       = {1},
      issn         = {1756-994X},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2023-01388},
      pages        = {48},
      year         = {2023},
      abstract     = {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.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.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.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 (Other) / Glioblastoma (Other) / Glycolysis (Other) /
                      Mesenchymal subtype (Other) / Myeloid (Other) / Recurrence
                      (Other) / Spatial transcriptomics (Other) / Wound response
                      (Other)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37434262},
      doi          = {10.1186/s13073-023-01207-1},
      url          = {https://inrepo02.dkfz.de/record/277461},
}