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Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas
Sophie Weil1, Matthias Osswald1, Gergely Solecki1
1Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurosurgery, University Hospital Mannheim, University Heidelberg, Mannheim, Germany.
Background:
Primary and adaptive resistance against chemo- and radiotherapy and local recurrence after surgery limit the benefits from these standard treatments in glioma patients. Recently we found that glioma cells can extend ultra-long membrane protrusions, "tumor microtubes" (TMs), for brain invasion, proliferation, and interconnection of single cells to a syncytium that is resistant to radiotherapy. We wondered whether TMs also convey resistance to the other 2 standard treatment modalities.
Methods:
Patient-derived glioblastoma stemlike cell (GBMSC) lines were implanted under a cranial window in mice. Longitudinal in vivo two-photon laser scanning microscopy was used to follow tumor growth, including the fate of single glioma cells over months.
Results:
After a cylindrical surgical lesion, GBMSCs increasingly extended TMs toward the lesion area, which contributed to the repopulation of this area over many weeks. In fact, an excessive "healing response" was observed in which tumor cell densities significantly exceeded those of unlesioned brain regions over time. Inhibition of TM formation and function by genetic targeting of growth associated protein-43 robustly suppressed this surgery-induced tumor growth reaction, in contrast to standard postsurgical anti-inflammatory treatment with dexamethasone. After one cycle of temozolomide chemotherapy, intra- and intertumoral heterogeneity of TM formation and interconnection was strongly associated with therapy response: when tumor cells were integrated in TM networks, they were more likely to resist chemotherapy.
Conclusion:
TMs can contribute to the resistance against standard treatment modalities in gliomas. Specific inhibition of TMs is a promising approach to reduce local recurrence after surgery and lower resistance to chemotherapy.
Insights
Glioma cells form tumor microtubes (TMs) that promote brain invasion and resistance to chemotherapy and radiotherapy. Inhibiting TMs offers a promising strategy to combat glioma recurrence and treatment resistance.
Area of Science:
- Neuro-oncology
- Cancer biology
- Cellular mechanisms of brain tumors
Background:
- Gliomas exhibit resistance to standard treatments like chemotherapy and radiotherapy, alongside local recurrence post-surgery.
- Tumor microtubes (TMs), ultra-long membrane protrusions, facilitate glioma cell invasion, proliferation, and form a radiotherapy-resistant syncytium.
- The role of TMs in resistance to chemotherapy and surgery-induced recurrence was investigated.
Purpose of the Study:
- To determine if tumor microtubes (TMs) contribute to glioma resistance against chemotherapy and radiotherapy.
- To evaluate the impact of TMs on local recurrence after surgical resection.
- To explore TMs as a therapeutic target for improving glioma treatment outcomes.
Main Methods:
- Patient-derived glioblastoma stem-like cell (GBMSC) lines were xenografted into mouse brains under a cranial window.
- Longitudinal in vivo two-photon laser scanning microscopy was employed to monitor tumor growth and cell behavior over extended periods.
- Genetic targeting of growth-associated protein-43 (GAP-43) was used to inhibit TM formation and function.
Main Results:
- Following surgical resection, GBMSCs extended TMs, driving significant tumor repopulation and exceeding normal brain cell densities.
- Inhibition of TM formation via GAP-43 targeting suppressed surgery-induced tumor regrowth, outperforming dexamethasone treatment.
- Tumor cells within TM networks demonstrated increased resistance to temozolomide chemotherapy, highlighting heterogeneity in treatment response.
Conclusions:
- Tumor microtubes (TMs) play a crucial role in mediating resistance to standard glioma treatments, including chemotherapy and radiotherapy.
- Targeting TMs presents a novel therapeutic strategy to mitigate local recurrence after surgery and overcome chemoresistance in gliomas.