In the September 9 cover article of Cancer Cell, researchers integrated 10x single cell and spatial technologies to identify a mechanism of glioblastoma recurrence in mice and develop a promising potential therapeutic approach.
PLEASANTON, Calif.
, Sept. 10, 2024 /PRNewswire/ -- 10x Genomics, Inc. (Nasdaq: TXG), a leader in single cell and spatial biology, announced today that its Chromium Single Cell Gene Expression and Xenium In Situ platforms were used in a publication – featured on the cover of Cancer Cell – that sheds light on the role of fibrotic scars in glioblastoma treatment recurrence. The study, led by researchers in the laboratory of Professor Johanna Joyce (University of Lausanne, Switzerland) and the Ludwig Institute for Cancer Research (Lausanne, Switzerland), also showcased how inhibiting both colony stimulating factor 1 receptor (CSF-1R; a therapeutic target under investigation for treating multiple cancers, including glioblastoma (GBM)) and the formation of fibrotic scars led to improved survival of mice in preclinical trials.
GBM is both the most common brain cancer and the most aggressive, with a five-year survival rate of less than 5%. Even with treatment, more than 90% of patients have their tumors recur. In this study, "Fibrotic Response to Anti-CSF-1R Therapy Potentiates Glioblastoma Recurrence," Professor Joyce and her team sought to understand the mechanisms behind GBM recurrence and how to improve existing therapies.
Using a mouse model of GBM as their starting point, the team first noticed that all GBM treatments they tested were associated with fibrosis – a type of scarring – in the brain. Notably, all recurrent tumors were found immediately adjacent to these fibrotic scars; high-plex protein analysis indicated these scars contained dormant tumor cells that the researchers believe act as seeds for GBM recurrence. They next used Chromium Single Cell Gene Expression to characterize cell populations in fibrotic scars at several time points post-treatment, then turned to single cell spatial transcriptomics with Xenium In Situ to reveal the location of cells within the scars.
"Assessing how the glioblastoma microenvironment responded to treatment was extremely challenging, because the spatial localization of all the cell types was so important," said Dr. Spencer Watson, co-first author and postdoctoral fellow in the Joyce lab at the University of Lausanne. "We generated very rich datasets: mass-spec proteomics, HIFI digital pathology and Chromium single cell RNA-seq. But what made all these disparate data so powerful was integrating them all together with Xenium single cell spatial transcriptomics. This allowed us to analyze the biology holistically, in ways that no single technique could do on its own."
Normally, T cells act to kill cancer cells. However, the data they generated using Xenium showed that while T cells interacted with GBM tumor cells throughout the tissue, the T cells inside fibrotic scars were much more likely to be exhausted (e.g. non-functional). This raised the possibility that these scars not only contained residual tumor cells but helped protect them from immune recognition, acting like a reservoir for GBM recurrence and presenting a potential therapeutic target.
Combining Xenium and Chromium, the researchers found that genes associated with the formation of these scars were highest in one specific cell type: pericyte-derived fibroblast-like cells. Focusing on these cells, they identified two critical pathways linked to scar formation that spiked seven days post-treatment, but dropped back down after fourteen days, suggesting therapeutic relevance for inhibiting fibrotic scar formation.
Using Chromium to narrow down potential druggable targets, the Joyce lab created a three-drug treatment regimen consisting of a CSF-1R inhibitor and two different drugs inhibiting scar formation. Over long-term preclinical trials, these drugs had little effect when administered separately. When combined, however, these treatments led to a dramatic increase in survival in mice, with only 1 in 18 mice experiencing tumor recurrence over the several-month-long trial – a vast improvement compared to conventional treatments. Professor Joyce said, "Strategies such as these to limit fibrotic scarring could significantly improve outcomes for GBM patients receiving surgical, radiation, or macrophage-targeting therapies; this is an area of active investigation in my lab."
Ben Hindson, Co-Founder and Chief Scientific Officer of 10x Genomics, said, "This paper by Watson, Zomer, Joyce, and colleagues is a powerful example of how integrating Xenium single cell spatial and Chromium scRNA-seq can completely reshape our understanding of cancer dynamics. Seeing not just how cancer develops, but where and in what context, enabled these researchers to develop a potential therapy in their preclinical work by leveraging the strengths and synergies of different technologies to generate insights that simply aren't possible with a single platform. Advances like these are why we continuously drive innovation to help researchers move science forward."
To learn more about the study, read the full article.
About 10x Genomics
10x Genomics is a life science technology company building products to accelerate the mastery of biology and advance human health. Our integrated solutions include instruments, consumables and software for single cell and spatial biology, which help academic and translational researchers and biopharmaceutical companies understand biological systems at a resolution and scale that matches the complexity of biology. Our products are behind breakthroughs in oncology, immunology, neuroscience and more, fueling powerful discoveries that are transforming the world's understanding of health and disease. To learn more, visit 10xgenomics.com or connect with us on LinkedIn or X (Twitter).
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