Metabolic reprogramming in glioblastoma: a rare case of recurrence to scalp metastasis

Abstract

Background: Glioblastoma (GB), an aggressive brain malignancy with a poor prognosis of 1.5-2 years, rarely exhibits extracranial metastasis (ECM). However, metabolic reprogramming has emerged as a key driver of GB progression and invasiveness. This study presents a rare case of recurrent GB with scalp metastasis, exploring how metabolic shifts enable GB cells to evade treatment and adapt to hostile environments, offering insights for developing innovative therapies.

Methods: Tandem mass spectrometry (MS/MS) was employed to analyze amino acid profiles in both the recurrent and metastatic stages of GB. Systems biology approaches were used to uncover genetic alterations and metabolic reprogramming associated with the progression from recurrence to metastasis.

Results: Our analysis revealed distinct amino acid utilization patterns in a patient with a molecular phenotype of wild-type IDH-1&2, TERT mutation, non-mutated BRAF and EGFR, and non-methylated MGMT. During recurrence and metastasis, significant differences in amino acid profiles were observed between blood and cerebrospinal fluid (CSF) samples. Additionally, protein-protein interaction (PPI) analysis identified key genomic drivers potentially responsible for the transition from recurrent to metastatic GB.

Conclusions: Beyond established risk factors such as craniotomy, biopsies, ventricular shunting, and radiation therapy, our findings suggest that metabolic reprogramming plays a crucial role in the transition from recurrent to metastatic GB. Targeting these metabolic shifts could provide new avenues for managing and preventing extracranial metastasis in GB, making this an important focus for future research.

Fig. 1. Imaging and histopathology of GB and Its metastasis to the scalp.

Axial (a), sagittal (b), and coronal (c) views of brain MRI before the second surgery, along with the postoperative counterparts (d–f). In the preoperative imaging, multicentric GB involving left posterior frontal and left temporoparietal regions concomitant with metastasis to the scalp of the left frontal area is seen. Compared to postoperative imaging, gross total removal (GTR) of the lesions has been obtained. g Hypercellular neoplastic glial tissue (blue arrow) with palisading necrosis (black arrow) and vascular proliferation (yellow arrow) (hematoxylin-eosin, x200). h Hypercellular neoplastic glial tissue (blue arrow) with vascular proliferation (yellow arrow) and palisading necrosis (black arrow) (hematoxylin-eosin, x200). i Neoplastic glial tissue (blue arrow) with invasion to muscle bundles (black arrow) (hematoxylin-eosin, x200). j Neoplastic glial tissue (blue arrow) invades muscle bundles (black arrow) (hematoxylin-eosin, x200).

Fig. 2. Immunohistochemical (IHC) staining in the patient’s recurrent and metastatic tumor.

IHC staining of the patient’s recurrent and metastatic glioblastoma (GB) tumor samples highlights the expression of markers associated with mesenchymal transition (EMT), including GFAP and vimentin. These markers indicate cellular plasticity, correlated with enhanced invasive potential and metastatic behavior in GB. Panels (a, h) show beta-catenin with negative (0) staining, indicating no detectable expression in the analyzed tumor cells, while panels (b, i) demonstrate desmin with negative (0) staining, reflecting its absence in the tumor. Panels (c, j) display strong positive (+3) staining for GFAP, suggesting potential involvement in tumor invasiveness. Panels (d, k) show myogenin with negative (0) staining, indicating its absence in the tumor, and panels (e, l) depict p53 with negative (0) staining, indicating no overexpression in the analyzed samples. Panels (f, m) highlight SMA with negative (0) staining, reflecting no significant expression. In contrast, panels (g, n) show vimentin with strong positive (+3) staining, supporting its role as a marker of mesenchymal transition in glioblastoma. Based on standardized scoring, each marker’s staining intensity is categorized as Negative (0) or Positive (+3). The combined positive staining for GFAP and vimentin provides evidence supporting mesenchymal transition and enhanced invasive and metastatic potential in GB. GFAP Glial Fibrillary Acidic Protein, SMA Spinal Muscular Atrophy, IDH1&2 Isocitrate dehydrogenase 1, WT wild-type, TERT Telomerase reverse transcriptase, MUT Mutated, EGFR Epidermal growth factor receptor.