Lausanne Researchers Use 10x Genomics' Chromium and Xenium to Study Brain Cancer Resistance and Therapies

In a groundbreaking study published on the cover of Cancer Cell on September 9, 2024, researchers have unveiled new insights into the recurrence of glioblastoma (GBM), the most common and aggressive form of brain cancer. This study, led by Professor Johanna Joyce from the University of Lausanne and the Ludwig Institute for Cancer Research, utilized advanced technologies from 10x Genomics to explore the role of fibrotic scars in GBM recurrence and propose a potential therapeutic strategy.

Glioblastoma is notorious for its poor prognosis, with a five-year survival rate of less than 5%. Despite treatment, over 90% of patients experience tumor recurrence. The study titled "Fibrotic Response to Anti-CSF-1R Therapy Potentiates Glioblastoma Recurrence" aimed to understand the underlying mechanisms of this recurrence and improve therapeutic approaches.

The research team used a mouse model to investigate various GBM treatments and observed an association between these treatments and fibrosis, a form of scarring in the brain. Significantly, recurrent tumors were often located near these fibrotic scars. High-plex protein analysis revealed that these scars contained dormant tumor cells, which likely acted as seeds for tumor recurrence.

To delve deeper, the team employed 10x Genomics' Chromium Single Cell Gene Expression platform to analyze cell populations in the fibrotic scars at different time intervals post-treatment. They also used the Xenium In Situ platform for single-cell spatial transcriptomics to map the location of cells within the scars.

Dr. Spencer Watson, a co-first author and postdoctoral fellow in Joyce’s lab, highlighted the importance of spatial localization of cell types when assessing the glioblastoma microenvironment's response to treatment. The integration of diverse datasets, including mass-spec proteomics, HIFI digital pathology, and single-cell RNA sequencing, allowed for a comprehensive analysis that single techniques alone could not achieve.

The data indicated that T cells, which typically act to eliminate cancer cells, were rendered non-functional or exhausted within the fibrotic scars. This finding suggested that the scars not only harbored residual tumor cells but also protected them from immune detection, thus serving as reservoirs for GBM recurrence.

Further analysis combining both Xenium and Chromium platforms highlighted that genes involved in scar formation were predominantly expressed in pericyte-derived fibroblast-like cells. These cells showed significant changes in pathway activities related to scar formation seven days post-treatment, which then declined after fourteen days, suggesting a critical window for therapeutic intervention.

The research team then identified potential drug targets using the Chromium platform and devised a three-drug regimen comprising a CSF-1R inhibitor and two agents inhibiting scar formation. While these drugs had minimal impact individually, their combination dramatically increased survival rates in mice, with only one of eighteen mice experiencing tumor recurrence over several months.

Professor Joyce emphasized that strategies to limit fibrotic scarring could greatly enhance outcomes for GBM patients undergoing surgery, radiation, or macrophage-targeting therapies. This promising approach is currently a focus of ongoing research in her lab.

Ben Hindson, Co-Founder and Chief Scientific Officer of 10x Genomics, praised the study as a testament to the power of integrating different single-cell technologies. By understanding not just how cancer develops but also where and in what context, the researchers were able to propose an effective preclinical therapy. This integration of technologies underscores the importance of continuous innovation in advancing the field of cancer research.

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