Researchers chart cellular complexity of brain tumors

June 12, 2014

Scientists from the Broad Institute and Massachusetts General Hospital (MGH) have conducted a first-of-its-kind study that characterizes the cellular diversity within glioblastoma tumors from patients. The study, which looked at the expression of thousands of genes in individual cells from patient tumors, revealed that the cellular makeup of each tumor is more heterogeneous than previously suspected. The findings, which appear online in Science Express, will help guide future investigations into potential treatments for this devastating disease.

This is the first time a large-scale census of the individual cells residing in these brain tumors has been taken. Researchers were previously aware that the cells within a human tumor were not all the same – they could have different mutations in their genome and possibly express genes differently – and it is suspected that this diversity may contribute to drug resistance and disease recurrence. But until now, it had been difficult to quantify the extent of this diversity.

To chart such differences, the researchers used a relatively new approach called single-cell transcriptomics, which allowed them to look at patterns in each of 430 individual cells from five patients' . These patterns, which vary from cell to cell, show which genes are switched on and which are switched off in a given cell, revealing information about the cell's nature and function.

Previous studies of glioblastoma looked at the average expression of genes across millions of cells, which were slurried together in a single sample. In some cases, this type of sampling is used to classify glioblastoma tumors into one of four recognized cancer sub-types, based on the gene expression program that is most prevalent. By examining the of many individual cells, one at a time, the team was able to get a finer picture of the cellular composition of the tumors. Their study revealed that each glioblastoma tumor contains from multiple cancer sub-types, and that the distribution of these cells varies from tumor to tumor.

The study also found that the cancer cells in these tumors exist in many states. Some are stem-cell-like, suggesting they have the capacity to self-renew and may play a role in tumor regeneration even after therapy. Others are the more mature, differentiated cancer cells that make up the bulk of the tumor. But the researchers also found that many cells exist on a spectrum between these states. Existing treatments, which only target the most prevalent cells in the tumor, may miss some of these sub-populations.

"To focus on the aspects of heterogeneity that we thought could be clinically relevant, we looked primarily for distinct cell states, and found multiple sub-populations in each tumor. Clinically, what this means is that we might need to treat each tumor based on the complement of cellular sub-types it contains – not just the most prevalent one," said co-senior author Aviv Regev. Regev is a Broad Institute core member and director of the Broad's Klarman Cell Observatory, as well as an associate professor at MIT and an Early Career Scientist with the Howard Hughes Medical Institute.

The researchers hope that these findings will help guide future investigations and approaches to treatment for glioblastoma, which is the most common and most aggressive form of in adults.

"This is an incurable disease. There are existing therapies that may target 99 percent of the cells, but the tumors always come back. Understanding the cellular landscape can provide a blueprint for identifying new therapies that target each of the various sub-populations of , and ultimately for tailoring such therapies to individual patient tumors," said co-senior author Bradley Bernstein. Bernstein is a senior associate member of the Broad and professor of pathology at Massachusetts General Hospital and Harvard Medical School. He is also an Early Career Scientist of the Howard Hughes Medical Institute and a principal investigator at the Broad's Klarman Cell Observatory.

In addition to Bernstein and Regev, the study was led by co-first authors Anoop Patel and Itay Tirosh, who are postdoctoral fellows in the Bernstein and Regev labs respectively, and co-senior author Mario Suvà, an assistant professor of pathology at MGH and a Broad associated scientist. The team represented a path-forging partnership between physicians and researchers from MGH's Departments of Neurosurgery and Pathology, and molecular and computational biologists at the Broad. The collaboration brought together neurosurgeons and pathologists at MGH, led by Patel and Suvà, who removed the tumors from patients and molecularly characterized the samples; Broad biologists, led by John Trombetta and Alex Shalek, who conducted the single-cell analysis; and a computational team, led by Tirosh, that analyzed the data.

The team anticipates that the method and collaborative model will be effective in characterizing other cancer types. Efforts to study additional cancers using the same methodology are currently underway.

Explore further: Researchers identify transcription factors distinguishing glioblastoma stem cells

More information: Patel, AP et al. "Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma." Science Express. Online June 12, 2014. DOI: 10.1126/science.1254257

Related Stories

Researchers identify transcription factors distinguishing glioblastoma stem cells

April 10, 2014
The activity of four transcription factors – proteins that regulate the expression of other genes – appears to distinguish the small proportion of glioblastoma cells responsible for the aggressiveness and treatment resistance ...

Multiple myeloma study uncovers genetic diversity within tumors

January 13, 2014
The most comprehensive genetic study to date of the blood cancer multiple myeloma has revealed that the genetic landscape of the disease may be more complicated than previously thought. Through results published in Cancer ...

Newly identified brain cancer mutation will aid drug development

June 1, 2014
A collaborative effort between Duke Medicine researchers and neurosurgeons and scientists in China has produced new genetic insights into a rare and deadly form of childhood and young adult brain cancer called brainstem glioma.

New tumor-targeting agent images and treats wide variety of cancers

June 11, 2014
Scientists at the University of Wisconsin Carbone Cancer Center (UWCCC) report that a new class of tumor-targeting agents can seek out and find dozens of solid tumors, even illuminating brain cancer stem cells that resist ...

Herpes-loaded stem cells used to kill brain tumors

May 16, 2014
(Medical Xpress)—Harvard Stem Cell Institute (HSCI) scientists at Massachusetts General Hospital have a potential solution for how to more effectively kill tumor cells using cancer-killing viruses. The investigators report ...

To stay a step ahead of breast cancer, make a map of the future

January 23, 2014
Cancer isn't a singular disease, even when talking about one tumor. A tumor consists of a varied mix of cells whose complicated arrangement changes all the time, especially and most vexingly as doctors and patients do their ...

Recommended for you

Cancer-death button gets jammed by gut bacterium

July 27, 2017
Researchers at Michigan Medicine and in China showed that a type of bacterium is associated with the recurrence of colorectal cancer and poor outcomes. They found that Fusobacterium nucleatum in the gut can stop chemotherapy ...

Researchers release first draft of a genome-wide cancer 'dependency map'

July 27, 2017
In one of the largest efforts to build a comprehensive catalog of genetic vulnerabilities in cancer, researchers from the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute have identified more than 760 genes ...

Long-sought mechanism of metastasis is discovered in pancreatic cancer

July 27, 2017
Cells, just like people, have memories. They retain molecular markers that at the beginning of their existence helped guide their development. Cells that become cancerous may be making use of these early memories to power ...

Blocking the back-door that cancer cells use to escape death by radiotherapy

July 27, 2017
A natural healing mechanism of the body may be reducing the efficiency of radiotherapy in breast cancer patients, according to a new study.

Manmade peptides reduce breast cancer's spread

July 27, 2017
Manmade peptides that directly disrupt the inner workings of a gene known to support cancer's spread significantly reduce metastasis in a mouse model of breast cancer, scientists say.

Glowing tumor technology helps surgeons remove hidden cancer cells

July 27, 2017
Surgeons were able to identify and remove a greater number of cancerous nodules from lung cancer patients when combining intraoperative molecular imaging (IMI) - through the use of a contrast agent that makes tumor cells ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.