Study Fueled by Xenium Analysis Sheds Light on Resistance Mechanisms in Model of Lethal Pediatric Brain Tumors

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Oct 26, 2023, 16:05 ET

Scientific pre-print featuring customer-generated data demonstrates the power of single cell spatial analysis to more directly assess unique tissue microenvironments and cell-cell interactions

PLEASANTON, Calif., Oct. 26, 2023 /PRNewswire/ -- 10x Genomics, Inc. (Nasdaq: TXG), a leader in single cell and spatial biology, announced today that the 10x Xenium Analyzer was used in a study recently published on bioRxiv characterizing radiation-resistance mechanisms of diffuse midline gliomas (DMGs). Led by researchers at Duke University, the study also provides a lens by which to understand clinical response in patients for current and future clinical trials using a novel kinase inhibitor as part of DMG therapeutic strategies.

The study, "Ataxia-telangiectasia mutated (Atm) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy," is among the first scientific preprints to include customer-generated data using the Xenium In Situ platform from 10x Genomics. The high-plex, high-resolution single cell spatial mapping of Xenium was behind many critical conclusions in this study, including revealing key transcriptomic changes, the role of specific tumor compartments, key cell communication pathways and the mechanisms by which key genes function within the therapeutic response.

Researchers conducting the study analyzed formalin-fixed paraffin-embedded tissue sections of a mouse brain tumor model that mimics the common human DMG genetic drivers and to examine the molecular and cellular mechanisms driving radiation efficacy or resistance in these tumors. The study put particular focus on the role that loss of Atm, which encodes a protein responsible for cellular response to double-stranded DNA damage, plays in treatment response.

"The single cell resolution enabled us to advance beyond deductive science," said Dr. Simon Gregory, co-senior author and Professor and Director of the Brain Tumor Omics Program in the Duke University Department of Neurosurgery and Director of the Molecular Genomics Core at the Duke Molecular Physiology Institute. "We were able to delve into the cellular composition of unique tumor compartments and quantify the spatial proximity between key cell types, revealing how the spatial relationship between tumor and immune cells changed in response to a new therapeutic intervention."

Dr. Zach Reitman, lead author and Assistant Professor of Radiation Oncology, Pathology and Neurosurgery, said, "These are diffuse tumors that infiltrate the normal brain. We wondered how malignant cells within the tumor would respond to treatments compared to those in the infiltrating edge. We were able to tease apart how specific cell types in specific locations, such as the tumor core and infiltrating edge, responded to different treatments. This approach could help us understand mechanisms of treatment efficacy, which will help us design future clinical trials and come up with combination therapies to overcome treatment resistance."

Ben Hindson, Co-founder and Chief Scientific Officer at 10x Genomics, said, "This is a powerful, groundbreaking discovery. It is awesome to see our customers using Xenium in their own labs with such an incredible and immediate impact. We look forward to seeing how researchers around the world continue to use 10x products to fuel discoveries that push our understanding of health and disease forward."

The authors began by generating several DMG mouse models and identifying the conditions under which Atm loss or pharmacological inhibition with brain-penetrant ATM inhibitor AZD1390 leads tumors to exhibit increased sensitivity to radiation. After these genetic experiments implicated tumor suppressor p53 loss as the principal driver of Atm loss–mediated sensitivity to radiation, the researchers used the pre-designed Xenium Mouse Brain Gene Expression Panel to profile key cell types in the brain and designed a Custom Add-on Panel to examine DMG-specific markers. The combination of the pre-designed and custom panels allowed researchers to profile compartment-specific gene expression changes of 298 targets at single cell resolution.

Irradiation treatment was observed to cause differential expression in cell cycle regulators and cell-fate-regulating transcription factors, while the combination of irradiation and Atm loss also impacted Semaphorin genes, which have been previously implicated in glioma proliferation and expansion. The researchers next estimated the distances between tumor cells and other cell types revealing neoplastic tumor cells could be found in closer proximity to certain immune cells as a result of Atm loss or irradiation, but this effect was most pronounced in Atm-null irradiated brains.

Additional analyses of the Xenium data revealed a complex interplay between p21 status, a downstream target of p53, and Atm-mediated radiosensitivity, leading the authors to emphasize the importance of considering an animal model's or patient's p21 status for clinical trials involving ATM inhibitors.

To learn more about this 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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