Study reveals startlingly different tissue sensitivities to cancer-driving genes

March 22, 2018, Harvard Medical School
Credit: CC0 Public Domain

New research led by Harvard Medical School and Brigham and Women's Hospital has unmasked hundreds of cancer-driving genes and revealed that different tissue types have shockingly variable sensitivities to those genes.

The findings, published online in Cell on March 22, promise to improve scientists' understanding of normal and malignant cell proliferation. They also help explain why individual drivers appear in some tumors and not others and could inspire more -specific strategies for cancer treatment.

"Genes that regulate pancreatic cancer make pancreatic proliferate but not , and vice versa," said the study's senior author, Stephen Elledge, professor of medicine at Brigham and Women's and the Gregor Mendel Professor of Genetics and of Medicine at Harvard Medical School. "The degree to which we see different cells respond to different genes is unprecedented."

Hidden players

Although a certain amount of cell growth and division, or proliferation, is essential for maintaining health, cancer steps on the gas pedal so cells proliferate with abandon.

Some genes drive harmful proliferation because they've been mutated. Other genes remain intact but still fuel tumor growth because they've been turned on too high or been duplicated.

This video shows mammalian cells proliferation. The colors represent different phases of the cell cycle. Credit: Teresa Davoli, Elledge lab, Harvard Medical School

Scientists have had a hard time identifying these overactive genes because they don't get flagged by genetic sequencing. Elledge's lab, along with colleagues at the Dana-Farber Cancer Institute and Baylor College of Medicine, devised another way to find them.

The researchers built a library of 30,000 individually bar-coded genes, representing about 80 percent of the genome. They took a collection of cells and put one gene into each of them. Instead of using 30,000 separate lab dishes, they let the cells grow in the same container. After a few days, the cells had proliferated at different rates. The researchers then used the bar codes to determine which genes drove growth.

The team ran the experiment on cells from three types of noncancerous tissue: breast cells, and connective-tissue cells called fibroblasts.

A full 10 percent of the genes tested turned out to regulate proliferation. Some had already been linked to cancer by DNA sequencing studies, but many more had not.

About 250 of the genes that hadn't been previously associated with normal or abnormal cell proliferation can be found in tumors where large segments of DNA are repeatedly amplified or deleted, "suggesting they help drive cancer," said Elledge.

More different than alike

Even more startling were the distinctive ways in which each tissue type responded to the same gene activity.

"We didn't realize how profoundly different the tissues would be," said Elledge. "The closest two were 90 percent different."

Genes that drove proliferation in one tissue often had no effect, or even suppressed proliferation, in another.

"That was shocking to me," said Elledge. "One family of genes made breast cells grow as fast as the greatest oncogene and did nothing in these other cells."

Analyses of gene expression in cancerous tissue reinforced the researchers' findings. They discovered that the genes that drove proliferation only in breast tissue matched patterns of gene activity seen in certain breast cancers. Similarly, genes that drove proliferation only in pancreatic tissue matched those seen in pancreatic tumors known as adenocarcinomas.

The results suggest that tissue type plays a larger role than previously appreciated in cancer genetics and should be taken into greater account when devising treatments that aim to curb , Elledge said.

The insight could explain why drugs that target the same proliferation driver sometimes work in some cancers but not others.

"This work sounds a note of caution to those who wish to develop therapies for all tissue types based on one driver mutation," Elledge said. "Just because a proliferation-targeting drug works in one tissue doesn't mean it will work elsewhere."

A broader atlas

How many more proliferation-driving genes lurk in the rest of the body's tissues? Do tissue types respond in unique ways to hallmarks of cancer other than ?

The researchers have made their tool available so that the scientific community can investigate these and other questions.

"There are so many cancers and so few treatments; we're still building our tool kit of therapies," said Elledge. "This work suggests it's worth paying attention to this whole new set of ."

Explore further: Can mice really mirror humans when it comes to cancer?

Related Stories

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

Study pinpoints gene's role in pancreatic cancer

August 11, 2017
Pancreatic cancer is a particularly deadly form of disease, and patients have few options for effective treatment. But a new Yale-led study has identified a gene that is critical to pancreatic cancer cell growth, revealing ...

Cancer may require simpler genetic mutations than previously thought

May 25, 2012
Chromosomal deletions in DNA often involve just one of two gene copies inherited from either parent. But scientists haven't known how a deletion in one gene from one parent, called a "hemizygous" deletion, can contribute ...

Shifting protein networks in breast cancer may alter gene function

November 30, 2017
A given gene may perform a different function in breast cancer cells than in healthy cells due to changes in networks of interacting proteins, according to a new study published in PLOS Computational Biology.

New cancer driver found: Monoclonal antibody therapy stops tumor growth in mice

May 8, 2013
(Medical Xpress)—Approximately 90 percent of cancers start within tissues that form the inner linings of various organs. Decades of accumulated genetic mutations can, on occasion, induce cells specialized for growth in ...

Pancreatic cancer development

September 1, 2017
Pancreatic ductal carcinoma (PDAC) is one of the most lethal types of cancer, with new therapeutic options needed.

Recommended for you

A single missing gene leads to miscarriage

October 19, 2018
A single gene from the mother plays such a crucial role in the development of the placenta that its dysfunction leads to miscarriages. Researchers from the Medical Faculty of Ruhr-Universität Bochum (RUB) have observed this ...

Making gene therapy delivery safer and more efficient

October 18, 2018
Viral vectors used to deliver gene therapies undergo spontaneous changes during manufacturing which affects their structure and function, found researchers from the Perelman School of Medicine at the University of Pennsylvania ...

Student develops microfluidics device to help scientists identify early genetic markers of cancer

October 16, 2018
As anyone who has played "Where's Waldo" knows, searching for a single item in a landscape filled with a mélange of characters and objects can be a challenge. Chrissy O'Keefe, a Ph.D. student in the Department of Biomedical ...

Researchers use brain cells in a dish to study genetic origins of schizophrenia

October 16, 2018
A study in Biological Psychiatry has established a new analytical method for investigating the complex genetic origins of mental illnesses using brain cells that are grown in a dish from human embryonic stem cells. Researchers ...

Why heart contractions are weaker in those with hypertrophic cardiomyopathy

October 16, 2018
When a young athlete suddenly dies of a heart attack, chances are high that they suffer from familial hypertrophic cardiomyopathy (HCM). Itis the most common genetic heart disease in the US and affects an estimated 1 in 500 ...

Importance of cell cycle and cellular senescence in the placenta discovered

October 15, 2018
Working with researchers from Stanford University and St. Anna Children's Cancer Research, researchers from Jürgen Pollheimer's laboratory at the Medical University of Vienna's Department of Obstetrics and Gynecology have ...


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.