Highlighting chromosomal deletion to move cancer research forward

22 October 2016
In a typical cancer cell, up to one-quarter of the genome is lost due to chromosomal deletions on a massive scale. The subsequent vulnerabilities can’t be revealed by studying these genes individually. By generating cells with chromosomal alterations that mimic human cancers, the team of Anna Sablina (VIB-KU Leuven) allows researchers to assess the role of particular chromosomal deletion in cancer development and progression.

While most cancer research studies individual genes or non-coding RNAs, Anna and her team went for the bigger picture by focusing on large-scale chromosomal deletion. Through chromosomal engineering, they managed to model aberrations that are commonly observed in cancer patients. Surprisingly, these deletions led to phenotypes that are completely different from what was found in studies of single genes or micro-RNAs. Anna and PhD students Yanyan Cai and Jonathan Crowther talk about the ins and outs of the project.

What does this mean for cancer research in general?
Anna: “It indicates that chromosomal deletions should be considered as distinct mutational events. Furthermore, I’m convinced that applying chromosomal engineering will make it possible to generate a library of human cells that represent the diversity of genomic abnormalities observed in cancer cells. Not only will this help us better understand the human cancer genome, it will also provide a useful platform for identifying drugs that are able to selectively kill tumor cells with a particular chromosomal abnormality.”

What were the major challenges of this project?
Anna: “To learn about cancer biology, you need to mimic alterations observed in cancer patients as closely as possible. Also, because I’ve never pursued such a high-risk project, it was quite challenging for me to convince both the ERC committee and my team members to take the leap.”
Jonathan: “For me, it was deciphering the association between chromosomal deletion and its effect on drug responses in breast cancer patients. Without the existence of pre-established cancer patients’ cohorts, such as The Cancer Genome Atlas (TCGA), we would have been hindered in identifying these associations.”

Yanyan, how long did it take to generate cell lines with chromosomal deletion?
Yanyan: “It took us over a year and a half. We tried many different approaches to increase the genome editing efficiency and to detect, isolate and screen modified clones. To be honest, it was quite a frustrating process.”

What factors contributed to the team’s success?
Yanyan: “First of all: persistence, because we liked the project so much, and our uncommon approach resulted in completely new information. The other crucial thing was the collaboration of several people with completely different backgrounds. For example, I learned a lot about time management and project coordination.”

Jonathan: “Working in a multidisciplinary group was certainly a big plus. As a bioinformatician, I had the pleasure of working with people with hands-on approaches to genome editing, cell culture
techniques, and molecular biology applications. This project certainly gave me a greater appreciation for molecular biology.”

Anna: “When I was describing the project to the evaluation committee, Sir Paul Nurse (Francis Crick Institute, London and member of VIB’s institutional advisory board) asked me whether I consider myself a biochemist or a geneticist. Along the way, I realized that you have to be both if you’re doing functional genomics.”


Publication
Cai, Crowther, et al.,
Cancer Cell 2016


Research


Anna Sablina (VIB-KU Leuven) and her team
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