Periodic Reporting for period 1 - GlioSurg (Role of astrogliosis in the recurrence of brain tumors after microsurgical resection)
Reporting period: 2022-10-01 to 2024-09-30
Malignant primary and secondary brain tumors are among the most lethal human cancers, with glioblastoma IDH-wildtype (GB) being the most aggressive and frequently occurring. GB has a median survival of only 8 months, with a 5-year survival rate of 6.9%. Standard treatment for GB includes microsurgical tumor resection, radiotherapy, and concurrent chemotherapy with temozolomide. Achieving gross total resection is critical to improving progression-free and overall survival. However, despite advances in microsurgery and fluorescence-guided resections with agents like 5-aminolevulinic acid (5-ALA), only about half of cases achieve macroscopic gross total resection. This difficulty is largely due to tumor location in functional brain areas, which complicates safe removal without neurological risk, as well as the infiltrative nature of GB, which often extends beyond MRI-visible areas. Even with aggressive treatment, chemoradiation struggles to eliminate residual, resistant GB cells, leading to frequent recurrence at the resection site. In fact, 85% of GB patients experience tumor recurrence at the margin of the resection cavity within months post-surgery.
Although extensive research has been devoted to understanding the complex heterogeneity of GB, the peritumoral region where recurrence occurs has not been adequately characterized in the early post-operative period. Additionally, while surgery remains a cornerstone of GB treatment, its effects on cellular plasticity and the surrounding tumor ecosystem are not fully understood, largely due to the absence of reliable, reproducible models for studying these processes.
Although extensive research has been devoted to understanding the complex heterogeneity of GB, the peritumoral region where recurrence occurs has not been adequately characterized in the early post-operative period. Additionally, while surgery remains a cornerstone of GB treatment, its effects on cellular plasticity and the surrounding tumor ecosystem are not fully understood, largely due to the absence of reliable, reproducible models for studying these processes.
We developed an advanced fluorescence-guided microsurgical resection model in mice that replicates each step of neurosurgery performed on GB patients. This model allows us to examine the effects of microsurgical resection on GB and to characterize both the significant remodeling of the tumor microenvironment (TME) and the adaptive cellular phenotype changes that occur post-surgery.
Using multiple preclinical models, both syngeneic and xenograft, we performed time-resolved analyses combining bulk and single-cell transcriptomics, proteomics, phosphoproteomics, immunohistochemistry (IHC), immunofluorescence (IF), and multiphoton intravital microscopy (IVM). Through these advanced methodologies, we observed that microsurgical resection activates hypoxia-driven pathways in residual glioblastoma cells and induces a pronounced proneural-to-mesenchymal transition (PMT). This transition is accompanied by substantial remodeling of the TME, particularly affecting immune response and vascular function, which is consistent with ischemic conditions following surgical intervention. These changes may reduce the efficacy and distribution of subsequent chemoradiotherapy, potentially impairing therapeutic outcomes by altering the tumor’s response to treatment.
This refined model and our findings provide critical insights into how GB cells and the TME respond to surgery, identifying potential mechanisms that could be targeted to improve post-surgical therapeutic efficacy.
Using multiple preclinical models, both syngeneic and xenograft, we performed time-resolved analyses combining bulk and single-cell transcriptomics, proteomics, phosphoproteomics, immunohistochemistry (IHC), immunofluorescence (IF), and multiphoton intravital microscopy (IVM). Through these advanced methodologies, we observed that microsurgical resection activates hypoxia-driven pathways in residual glioblastoma cells and induces a pronounced proneural-to-mesenchymal transition (PMT). This transition is accompanied by substantial remodeling of the TME, particularly affecting immune response and vascular function, which is consistent with ischemic conditions following surgical intervention. These changes may reduce the efficacy and distribution of subsequent chemoradiotherapy, potentially impairing therapeutic outcomes by altering the tumor’s response to treatment.
This refined model and our findings provide critical insights into how GB cells and the TME respond to surgery, identifying potential mechanisms that could be targeted to improve post-surgical therapeutic efficacy.
Our work has advanced the understanding of how microsurgical resection impacts glioblastoma (GB) at both the cellular and microenvironmental levels, providing new insights that go beyond the current state of the art. The refined fluorescence-guided resection model in mice allows us to study the immediate effects of surgery on GB in real-time, revealing dynamic changes in the tumor’s phenotype, immune response, and vascular function. These findings challenge existing paradigms by highlighting how surgical resection not only impacts the tumor cells directly but also triggers profound and potentially detrimental changes in the tumor microenvironment (TME), which may hinder the success of subsequent therapies like chemoradiation.
Our discovery of hypoxia-driven pathways and the proneural-to-mesenchymal transition (PMT) after surgery represents a critical step in understanding the resilience mechanisms GB uses to evade treatment, suggesting that future therapies must not only target the tumor but also the altered TME post-surgery. This insight could have broad implications for improving current surgical and therapeutic strategies, emphasizing the need to develop treatments that address these changes and improve the effectiveness of chemoradiotherapy after resection.
Our discovery of hypoxia-driven pathways and the proneural-to-mesenchymal transition (PMT) after surgery represents a critical step in understanding the resilience mechanisms GB uses to evade treatment, suggesting that future therapies must not only target the tumor but also the altered TME post-surgery. This insight could have broad implications for improving current surgical and therapeutic strategies, emphasizing the need to develop treatments that address these changes and improve the effectiveness of chemoradiotherapy after resection.