A groundbreaking study from Ludwig Cancer Research Center has revealed a potential mechanism for the recurrence of glioblastoma multiforme (GBM), an aggressive brain cancer that has an average survival of just 14 months even after comprehensive treatment including surgery, radiation therapy, and immunotherapy.

The study, led by Johanna Joyce, Spencer Watson, and alumnus Anoek Zomer of the Ludwig University of Lausanne, was published in the cover article of the journal Cancer Cell. The research team found that recurrent tumors often originate from fibrous scars of malignant precursors formed after treatment. Instead of promoting normal healing, these scars become a shelter for tumor cells.

The research team used advanced techniques, including single-cell gene expression analysis, comprehensive tissue protein analysis, and ultra-complex immunofluorescence imaging (HIFI), to reveal the formation process of fibrotic scars. They found that these scars are actually a protective layer for residual cancer cells, allowing them to enter a dormant state and thus become resistant to treatment.

In addition, the study found that the progeny of cells associated with the blood vessels supplying the tumor were functionally altered to form cells similar to fibroblasts, which mediate the production of fibrotic scars in the tumor area. These cells were particularly activated by neuroinflammatory and immune factors, especially transforming growth factor-β (TGF-β).

Previous studies from the Joyce lab have demonstrated that immune cells can be reprogrammed to fight tumors by inhibiting signaling of the colony stimulating factor 1 receptor (CSF-1R). However, about half of the mice relapsed after initial treatment. The current study further explored how fibrotic scarring leads to relapse and designed a new treatment regimen that significantly prolonged survival in GBM mouse models by blocking TGF-β signaling and inhibiting neuroinflammation, combined with CSF-1R inhibition.

The researchers said the findings provide new ideas for improving treatment outcomes for glioblastoma patients. Methods to limit fibrotic scarring could significantly improve survival in patients who undergo surgery, radiation therapy, or macrophage-targeted therapy. They also noted that future studies could identify better drug targets to further optimize this combination therapy.

This study not only provides new strategies for the treatment of glioblastoma, but also provides valuable insights into the broader study of tumor recurrence mechanisms. By gaining a deeper understanding of the tumor microenvironment, scientists hope to develop more effective treatments to fight this deadly disease.