Tumor Edge-to-Core Transition Promotes Malignancy in Primary-to-Recurrent Glioblastoma Progression in a PLAGL1/CD109-mediated mechanism

Abstract

BackgroundGlioblastoma remains highly lethal due to its inevitable recurrence. This recurrence is found locally in most cases, indicating that post-surgical tumor-initiating cells (TICs) accumulate at tumor edge. These edge TICs then generate recurrent tumors harboring new core lesions. Here, we investigated the clinical significance of the edge-to-core transition (ECT) signature causing glioblastoma recurrence and sought to identify central mediators for ECT.MethodsFirst, we examined the association of the ETC-related expression changes and patient outcome in matched primary and recurrent samples (n=37). Specifically, we tested whether the combined decrease of the edge TIC marker PROM1 (CD133) with the increase of the core TIC marker CD109 representing ECT during the primary-to-recurrence progression indicates poorer patient outcome. We then investigated the specific molecular mediators that trigger tumor recurrence driven by the ECT signature. Subsequently, the functional and translational significance of the identified molecule was validated within our patient-derived tumor edge-TIC models in vitro and in vivo.ResultsPatients exhibiting a CD133down/CD109up signature during recurrence representing ECT displayed a strong association with poorer progression-free survival and overall survival among all tested patients. Differential gene expression identified that PLAGL1 was tightly correlated with the core TIC marker CD109 and was linked to a shorter survival of glioblastoma patients. Experimentally, forced PLAGL1 overexpression enhanced, while its knockdown reduced, the glioblastoma edge-derived tumor growth in vivo and subsequent mouse survival, suggesting its essential role in the ECT-mediated glioblastoma development.ConclusionsECT is likely an ongoing lethal process in primary glioblastoma contributing to its recurrence partly in a PLAGL1/CD109-mediated mechanism.Key PointsECT is a pathobiological process contributing to glioblastoma lethalityThe CD133down/CD109up signature is a novel prognostic molecular biomarker in ECTPLAGL1 regulates growth of edge-located tumor-initiating cellsImportance of the StudyVery few studies have sought to longitudinally characterize the transition of molecular landscapes from primary to recurrent glioblastoma. Post-surgical edge-located TICs are presumably the predominant source of tumor recurrence, yet this cellular subpopulation in glioblastoma remains largely uncharacterized. This study evaluates the significance of glioblastoma edge-derived core transition (ECT) for tumor recurrence in the primary-recurrent paired sample set. We elucidate a prognostically-significant shift in molecular and cellular phenotypes associated with ECT in the CD133down/CD109up group. Moreover, our results provide clinical and experimental evidence that PLAGL1 is a mediator of glioblastoma ECT and its subsequent tumor development by the direct transcriptional regulation of the core TIC marker CD109.

CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity

“…JCI Insight 2021;6(9):e141486 https://doi.org/10.1172/jci.insight.141486 maintenance and disease recurrence (21,22). However, the precise mechanisms of how CD109 regulates these phenomena and implications for GSC biology remained unknown.…”

Spatial heterogeneity of glioblastoma cells reveals sensitivity to NAD+ depletion at tumor edge

“…1a and Extended Data Fig. 1a, b ) 5,6,9 In particular, ptEdge were secured from the deeper subcortical area of the brain, one of the most frequent brain regions to cause post-craniotomy tumor recurrence 4,19 . ptCore- and ptEdge-derived single cells were then labeled with lentiviral vectors to express green fluorescence protein (GFP) or mCherry, respectively ( Fig.…”

“…From a clinical standpoint, it remains to be proven whether ptEdge clones are capable of evolving into trans-ptEdge and subsequently to ptCore clones in vivo, especially in response to radiation and chemotherapy. Treatment-naive tumor edge and core cells express distinct key transcription factors 4 , activated kinases 6 and metabolites 9 . Post-surgical selection pressure by chemo-radiation causes secondary dynamic changes to these molecules in the remaining tumor edge cells, particularly in those that initiate tumor (core) recurrence/relapse.…”

“…Likewise, data in multiple murine glioblastoma-like tumor models has supported this Edge-to-Core (E-to-C) progression theory 3 . In addition, the clinical significance of the E-to-C molecular axis was indicated in the primary-to-recurrent glioblastoma setting with our cohort 4 . However, whether this theory universally explains the development of primary glioblastoma remains unknown.…”