A team of researchers from Weill Cornell Medicine, together with New York Genome CenterHarvard Medical SchoolMassachusetts General Hospital, and the Broad Institute of MIT and Harvard has profiled in unprecedented detail thousands of individual cells sampled from patients’ brain tumors.

The findings, along with the methods developed to obtain them, represent a significant advance in cancer research.  The researchers believe that their results may ultimately lead to better ways of detecting, monitoring, and treating cancers.

In an article, published in the September 30, 2021 edition of Nature Genetics, the researchers report that they used advanced techniques to record gene mutations, gene activity, and gene-activity-programming marks on DNA called methylations, within individual tumor cells sampled from patients with gliomas, the most common type of brain cancer.

The researchers mapped the distinct behavior or “states” of tumor cells in gliomas and identified key programming marks that appear to shift glioma cells from one state to another. These programming marks could, the researchers believe,  be targeted with future drugs.

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Ancestral trees
Combining their single-cell methods with a molecular-clock technique, the researchers created s0-called “ancestral trees” for the sampled tumor cells, depicting their histories of state changes.

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“It’s like having a time machine—we can take a sample from a patient’s tumor and infer many details of how that tumor has been developing,” said co-senior author Dan Avi Landau, MD, Ph,D, an associate professor of medicine in the Division of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and a core member of the New York Genome Center.

“We’ve been able to make observations here that have fundamental implications for how we should think about treating gliomas,” noted  Mario Suva, MD, Ph.D., co-senior of the study, who is an associate professor of pathology at Harvard Medical School, a pathologist at Massachusetts General Hospital and a member of the Broad Institute of MIT and Harvard.

A different approach
Tumors cells traditionally have been characterized in bulk, rather than individually, and in relatively simple ways, for example by their cell type of origin and by the receptors they bear on their surfaces. Landau and Suva, however, have helped pioneer the use of “single-cell multi-omics” methods to profile tumor cells individually and in much more detail.

In the new study, Landau and Suva used a three-layer method—recording not only gene sequence and gene transcription information but also ‘epigenetic’ transcription-controlling methylation marks on DNA. This was the first time researchers used this method on individual tumor cells directly from patients. The scientists sampled more than 100 tumor cells on average from each of seven patients with so-called IDH-mutant glioma, and from seven patients with a more treatment-resistant glioma called IDH-wildtype glioblastoma.

The researchers found that the cells in both cancers tended to be in one of four distinct states, ranging from stem-cell-like states to states like those of more mature brain cells. They also identified distinct patterns of DNA methylation, an epigenetic mechanism used by cells to control gene expression, that appear to account for shifts between these states; such patterns in principle could be disrupted with future therapies to suppress such ‘state changes’ and slow tumor development.

Snapshot
Although the researchers’ captured what was essentially a snapshot of cell states in the sampled tumors, they also devised a molecular clock method, based on the random changes in DNA methylations that naturally occur over time, to calculate a lineage tree for each cell—depicting its history of different states, going back to the origin of the tumor.

The lineage trees revealed among other things that glioblastoma cells, compared to cells from the lower-grade gliomas, had a high degree of ‘plasticity’ allowing them relatively easily switch back and forth between stem-like states and more mature states.

“The very plastic cellular architecture of IDH-wildtype glioblastoma may allow it to survive stem-cell-killing treatments by regenerating those cells from its pool of more mature cells,” said co-first author Federico Gaiti, Ph.D., a postdoctoral fellow in the Landau laboratory.

Novel insights
The findings in general offer a wealth of insights about the dynamics of gliomas, insights that should be useful in developing better methods for detecting, staging, monitoring and treating them.

The researchers now plan to use their single-cell multi-omics approach to study how gliomas respond to different treatments. In principle, they said, the approach can be used to study the development of any type of tumor, or even of genetic mutations that accrue with age in healthy tissues.

Dan Landau is an equity holder, co-founder, and paid scientific advisory board member for C2i Genomics and an equity holder and paid scientific advisory board member for Mission Bio. Dr. Mario Suva is an equity holder, scientific cofounder, and advisory board member of Immunitas Therapeutics.

Reference
[1] Chaligne R, Gaiti F, Silverbush D, Schiffman JS, Weisman HR, Kluegel L, Gritsch S, Deochand SD, Gonzalez Castro LN, Richman AR, Klughammer J, Biancalani T, Muus C, Sheridan C, Alonso A, Izzo F, Park J, Rozenblatt-Rosen O, Regev A, Suvà ML, Landau DA. Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states. Nat Genet. 2021 Sep 30. doi: 10.1038/s41588-021-00927-7. Epub ahead of print. PMID: 34594037.

Featured image: Illustration of a brain tumor. Photo Courtesy: © 2021 Weill Cornell Medicine/Shutterstock. Used with permission.

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