Powerful technique details brain tumors' formidable resiliency

Date:
October 1, 2021
Source:
Weill Cornell Medicine
Summary:
A team led by researchers has profiled in unprecedented detail
thousands of individual cells sampled from patients' brain
tumors. The findings, along with the methods developed to obtain
those findings, represent a significant advance in cancer research,
and ultimately may lead to better ways of detecting, monitoring
and treating cancers.



FULL STORY ==========================================================================
A team led by researchers at Weill Cornell Medicine, the New York Genome Center, Harvard Medical School, Massachusetts 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 those findings,
represent a significant advance in cancer research, and ultimately may
lead to better ways of detecting, monitoring and treating cancers.


==========================================================================
As the researchers reported Sept. 30 in Nature Genetics, 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. In this way they mapped distinct tumor
cell behaviors or "states" in gliomas, and identified key programming
marks that appear to shift glioma cells from one state to another. These programming marks, in principle, could be targeted with future drugs.

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

"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 Dr. Dan Landau, 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," said
co-senior author Dr.

Mario Suva, 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.

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. Drs. 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 they used a three-layer method -- recording not only
gene sequence and gene transcription information but also "epigenetic" transcription-controlling methylation marks on DNA -- for the first
time 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.

They 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 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.

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 to 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
Dr. Federico Gaiti, a postdoctoral fellow in the Landau laboratory.

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.

Dr. 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.

========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ronan Chaligne, Federico Gaiti, Dana Silverbush, Joshua
S. Schiffman,
Hannah R. Weisman, Lloyd Kluegel, Simon Gritsch, Sunil D. Deochand,
L.

Nicolas Gonzalez Castro, Alyssa R. Richman, Johanna Klughammer,
Tommaso Biancalani, Christoph Muus, Caroline Sheridan, Alicia
Alonso, Franco Izzo, Jane Park, Orit Rozenblatt-Rosen, Aviv Regev,
Mario L. Suva`, Dan A. Landau. Epigenetic encoding, heritability and
plasticity of glioma transcriptional cell states. Nature Genetics,
2021; DOI: 10.1038/s41588- 021-00927-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211001130236.htm

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