The map is the result of one of the biggest efforts in biological science: to construct a comprehensive catalog of genetic vulnerabilities in cancer. The outcome, which also appears as a visual gene map, was put together by researchers from the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute. These instiutions have come together as part of the Cancer Dependency Map initiative.
Using this type of information, startups are applying innovative techniques to seek to cure the common cold, re-engineer the human microbiome, and, in the context of the research highlighted in this article, to fight against cancer.
With the new research, the combined research teams have identified over 760 genes upon which cancer cells, from multiple types, are highly dependent for their growth and survival. Knowing this will help to reveal targets for new anti-cancer drugs. While 90 percent of the so-termed ‘dependencies’ are specific to particular types of cancer; 10 percent of those identified are common across multiple cancers. The implications of these relationships are that a relatively small number of therapies should be able to target these core dependencies and be capable of combatting several tumors.
The dependencies were detected by conducting genome-wide RNA interference (RNAi) screens. These screens were run against 501 cell lines, which represented 20 types of cancer. The process examined over 17,000 genes individually in each line. This showed the genetic dependencies unique to the cancerous cells.
RNA interference is a biological process where RNA molecules inhibit gene expression by neutralizing targeted mRNA molecules. Messenger RNA (mRNA) is a large family of RNA molecules that convey genetic information from DNA to the ribosome, where they specify the amino acid sequence of the protein products of gene expression. RNAi has considerable potential in suppression of desired genes. With this, two types of small ribonucleic acid (RNA) molecules – microRNA (miRNA) and small interfering RNA (siRNA) – are key to RNA interference. To execute a genome-wide RNAi screen, scientists expose cells to pools of siRNAs and track the cells’ behavior.
The reason why the research matters is because cancer cells harbor a range of genetic errors. If an error shuts down a critical gene, the cancerous cell will compensate by adjusting the activity other genes; and this leads to a dependence developing on such adaptations in order to persist. Thus by screening for these dependencies, the vulnerabilities of cancerous cells can be detected, through the determination of new therapeutic targets. This is based on researchers deploying genetic and small molecule perturbation technologies in order to triangulate relationships between genomic features and, what are effectively, “Achilles’ heels” across a wide-array of cancer types. With reference to the Greek myth, there is a related initiative called ‘Project Achilles’. This is a systematic effort aimed at identifying and cataloging gene essentiality across hundreds of genomically characterized cancer cell lines. The project makes use of genome-scale RNAi and CRISPR-Cas9 genetic perturbation reagents, aimed at knocking-out individual genes and identify those genes that affect cell survival.
Discussing this with Laboratory Manager magazine, William Hahn chief of the Division of Molecular and Cellular Oncology at Dana-Farber explains: “Much of what has been and continues to be done to characterize cancer has been based on genetics and sequencing. That’s given us the parts list.”
He goes onto add: “Mapping dependencies ascribes function to the parts and shows you how to reverse engineer the processes that underlie cancer.”
The map and big data analysis revealed interesting patterns in cancer cells’ dependencies. Given that over 90 percent of the cell lines had a strong dependency on one of 76 genes this suggests that many cancers rely on a relatively few genes and pathways. By running sophisticated computations based on a set of molecular features (such as mutations, gene copy numbers, expression patterns and so on) in relation to each cell line, the researchers additionally produced a biomarker-based model to help explain the biology behind 426 of the 769 dependencies.
This initial taxonomy is a the starting point for building a full map and the process will help scientists to decide where to focus their efforts for drug development as well as generating a comprehensive cancer dependency map. The map and the research outcomes are published in the science journal Cell. The research paper is titled “Defining a Cancer Dependency Map.”
In related news, a UC San Diego-led research team has put the hot gene-editing technology CRISPR/Cas9 to a novel use, finding more than 120 new leads for cancer drugs. With the gene editing technology, large numbers of genes can be tested simultaneously for their effect on cancer. CRISPR was recently in the news for more controversial reasons in relation to embryo cell editing, as reported by Digital Journal (see: “First U.S. case of human embryo gene editing.)
Essential Science
This article is part of Digital Journal’s regular Essential Science columns. Each week Tim Sandle explores a topical and important scientific issue. Last week we looked a new map of the dark matter of the universe taken using one of the most advanced telescopes in the world. The week before we peaked into the controversial scientific development associated with gene editing.
