title: Characterization of inter- and intratumoral heterogeneity and the differential immune microenvironment during malignant progression in meningiomas
creator: Blume, Christina
subject: ddc-500
subject: 500 Natural sciences and mathematics
description: Meningiomas are thought to arise from the arachnoid cells of the leptomeninx and make up the most common primary intracranial tumor in adults. They are usually benign, however in about 20 % of cases, tumors present with an aggressive phenotype and higher risk of recurrence. Risk stratification thereby remains challenging especially for NF2-mutated meningiomas, which make up  about  two  thirds  of  all  cases,  as  they  can  occur  at  the  full  spectrum  of  WHO  grades  in meningioma  from  1  to  3.  Recently,  molecular  profiling  has  gained  importance  for  prognosis  in meningioma with several classification systems that have been established mostly based on the DNA methylation of the tumors. However, the DNA methylation-based classification has not been extensively  linked  to  phenotypic  traits  of  the  tumor.  Nor  have  meningiomas  been  investigated regarding  intratumoral  subpopulations  that  may  exist  in  parallel  and  may  have  different characteristics, especially regarding the stage of progression and ability to recur. In addition, the role  of  the  immune microenvironment  in  meningiomas  is  poorly  understood,  despite  the identification  of  an  immune-enriched  meningioma subgroup  with  beneficial  outcome  in  two independent DNA methylation classification systems.   In this dissertation, I investigated the consistency of subgroups initially defined on epigenomic level  across  molecular  levels  by  comparison  to  transcriptomic  and  proteomic  data.  Further,  I leveraged  single  nuclei  transcriptomic  profiling  to  dissect  intertumoral  differences  in  the expression profile specific to the tumor cell population depending on the tumor subgroup, and to investigate  the  abundance  and  phenotype  of intratumoral  tumor  cell  subpopulations  across samples.  Similarly,  I  analyzed  the  single  nuclei  transcriptomic  data  to  characterize  tumor-infiltrating  immune  cells  with  respect  to  their  abundance  and  activation  status.  I  furthermore correlated the differences in immune infiltration with the progression-free survival of patients by deconvoluting DNA methylation array data according to their cellular composition.   These  analyses  underlined  the  coherence  of  epigenomic  meningioma  subgroups  across transcriptome  and  proteome.  Moreover,  I  identified  six  tumor  cell  subpopulations  that  were defined  by  distinct  expression  profiles  und  could  be  identified  across  samples  at  varying abundancies depending on the stage of progression. Similarly, I observed profound differences in infiltrating  immune  cells  between  tumor  subgroups,  with  a  significant  enrichment  of  tumor-associated macrophages in a benign subgroup of NF2-mutated meningiomas as compared to more progressed tumors. In parallel to their abundancy, macrophages changed in activation between benign  and  malignant  cases  from  an  anti-  to  a  pro-tumorigenic  phenotype.  The  evaluation of progression-free  survival  data  revealed  a  positive  correlation  to  the  proportion  of  infiltrating immune cells as estimated from epigenomic profiles.   Altogether, these results highlight the role of multi-level molecular profiling for tumor grading in a paradigmatic, epidemiologically relevant tumor type. They further indicate an important role of tumor-infiltrating macrophages during meningioma progression with possible consequences for risk prediction as well as therapeutic targets in meningioma.
date: 2023
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/33899/1/CBlume_Thesis.pdf
identifier: DOI:10.11588/heidok.00033899
identifier: urn:nbn:de:bsz:16-heidok-338994
identifier:   Blume, Christina  (2023) Characterization of inter- and intratumoral heterogeneity and the differential immune microenvironment during malignant progression in meningiomas.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/33899/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng