Researchers chart global genetic interaction networks in human cancer cells

February 2, 2017, Whitehead Institute for Biomedical Research
Using genome-wide CRISPR screens, Wang et al. identified clusters of genes that act together to carry diverse sets of biological processes that support cell survival and proliferation. Credit: Sigrid Knemeyer

Cancer is a heterogeneous disease, with myriad distinct subtypes that differ in their genetic roots. As a result, cancers rely on varied pathways for survival—and respond differently to anticancer agents. The challenge for researchers is to precisely define those diverse pathways and pinpoint vulnerabilities that may serve as drug targets for new anti-cancer treatments.

Investigators at Whitehead Institute and the Broad Institute have taken an important step in tackling that challenge: They have succeeded in identifying the set of essential genes—those required for cellular proliferation and survival—in each of 14 human (AML) cell lines that had previously been characterized by genome sequencing. By combining their "gene essentiality map" with the existing genomic information, their study revealed liabilities in genetically defined subset of cancers that could be exploited for new therapies.

The report on their work, appearing in the online edition of Cell, is entitled, Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras.

A major aspect of the study focuses on the genes and protein pathways connected to the Ras oncogene, the most commonly mutated oncogene in human cancers which plays a role in AML as well as many other cancers. "For the most part, the mutant Ras protein itself has been considered to be 'undruggable'," explain Tim Wang, the paper's first author and an MIT graduate student researcher at Whitehead Institute and the Broad Institute. "An alternative approach has been to find other genes that Ras-mutant cancers rely on with the hope that one of them may be druggable. Unfortunately, such 'Ras-synthetic-lethal' genes have been difficult to identify,." notes Wang.

Using CRISPR-based gene editing technique, the researchers could gauge the impact of individually knocking out each of the 18,000 protein-coding genes in the human genome. "This process rapidly enabled us to identify the short list of genes that were selectively required in only the Ras-mutant cells," explained David Sabatini, a senior author on the paper, as well as a Member of the Whitehead Institute, Pprofessor of Biology at MIT, and an investigator of the Howard Hughes Medical Institute. "We think this general approach can be applied to find vulnerabilities in many more cancer types."

In addition to defining the Ras-specific gene essentiality network, the data generated from this study also allowed the researchers to decipher the molecule function of previously unstudied genes. They started by focusing in on genes that were essential in some of the cell lines but dispensable for others. For each of these genes, the researcher sifted through their data to find others that showed a matching pattern of essentiality with the idea that all of them had similar functions. Indeed, this 'guilt-by-association' analysis revealed gene groups that were already known to act together and uncovered novel associations between genes that were not known to be related or had been previously unstudied.

"What's particularly exciting about this work is that we have just begun to scratch the surface with our method," Wang concludes. "By applying it broadly, we could reveal a huge amount of information about the functional organization of human and their roles in many diseases."

Explore further: CRISPR screening identifies potential HIV treatment targets

More information: Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras, Cell (online publication), Feb. 2, 2017

Related Stories

CRISPR screening identifies potential HIV treatment targets

December 19, 2016
Investigators from Whitehead Institute, the Ragon Institute of MGH, MIT and Harvard and the Broad Institute of MIT and Harvard have used CRISPR-Cas9 gene-editing technology to identify three promising new targets for treatment ...

Screen of human genome reveals set of genes essential for cellular viability

October 15, 2015
Using two complementary analytical approaches, scientists at Whitehead Institute and Broad Institute of MIT and Harvard have for the first time identified the universe of genes in the human genome essential for the survival ...

Vulnerabilities of leukemia cells revealed using genome editing technique

October 18, 2016
Researchers from the Wellcome Trust Sanger Institute and their collaborators have adapted a CRISPR gene editing technique and used it to find new therapeutic targets for acute myeloid leukaemia (AML). In research published ...

Researchers investigate new strategy to block growth of colon cancer cells

September 21, 2016
Researchers from Boston University School of Medicine (BUSM) have discovered a possible strategy to treat colon cancers that are caused by the mutant KRAS gene, which is responsible for approximately half of all colon cancer ...

Recommended for you

'Kiss of death' cancer: How computational geeks may have uncovered a therapy for a deadly disease

June 19, 2018
It's called the 'kiss of death'. Triple negative breast cancer has no targeted drug therapy and, as such, the only hope for these patients is chemotherapy. Triple negative breast cancer is aggressive and deadly. Patients ...

Ovarian cancer cells switched off by 'unusual' mechanism

June 19, 2018
Scientists at the Ovarian Cancer Action Research Centre at Imperial College London have discovered a mechanism that deactivates ovarian cancer cells.

Team discovers gene mutations linked to pancreatic cancer

June 19, 2018
Six genes contain mutations that may be passed down in families, substantially increasing a person's risk for pancreatic cancer. That's according to Mayo Clinic research published in the June 19 edition of the JAMA. However, ...

Breast cancer could be prevented by targeting epigenetic proteins, study suggests

June 19, 2018
Researchers at the Princess Margaret Cancer Centre in Toronto have discovered that epigenetic proteins promote the proliferation of mammary gland stem cells in response to the sex hormone progesterone. The study, which will ...

Targeting the engine room of the cancer cell

June 18, 2018
Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug ...

Study suggests well-known growth suppressor actually fuels lethal brain cancers

June 18, 2018
Scientists report finding a potentially promising treatment target for aggressive and deadly high-grade brain cancers like glioblastoma. But they also say the current lack of a drug that hits the molecular target keeps it ...

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.