This week we profile a recent publication in Science from Drs. Neil Umbreit (pictured below), Cheng-Zhong Zhang (pictured below), and the laboratory of Dr. David Pellman (pictured above) at Dana-Farber Cancer Institute and Harvard Medical School.
Can you provide a brief overview of your lab’s current research focus?
Neil Umbreit
My group studies cell division and the consequences of cell division errors for the structure of the genome. We focus on the origin of highly complex cancer genomes. Traditionally, genome evolution has been thought to occur slowly and gradually in the way that Darwin envisioned. However, recent work from us and others has identified processes that drive very rapid genome evolution through catastrophic mutational events (big bang-like events). We design experiments to recreate these events in the laboratory so that we can understand how they work. Often, we use a combination of live cell imaging and high-depth single cell genome sequencing that we call “look-seq”.
What is the significance of the findings in this publication?
This paper addresses the mechanism for a mutational process called the chromosome breakage-fusion-bridge cycle (BFB cycle). The BFB cycle was first described in the late 1930s and early 1940s by the celebrated scientist, Barbara McClintock, who showed that it could cause instability of the genome and increased amounts of the DNA at the ends of chromosomes (gene amplification). The BFB cycle is widely considered to be a major event in the generation of many cancers, but puzzlingly, in cancer genomes, the simplest predictions of the model in terms of chromosome structure are not commonly observed. What is observed in cancer genomes is typically far more complex rearrangement of the chromosomes.
Cheng-Zhong Zhang
Our paper has two take home points that I think are of general interest. First, we explain the complexity of BFBs by showing that BFBs are inherently interwoven with another catastrophic mutational process called chromothripsis. Chromothripsis is massive fragmentation and rearrangement of only one or a few chromosomes. Hints that these processes might be related were suggested by earlier studies, but our paper establishes that this cannot be explained by a coincidence but is an inevitable consequence of how BFBs work. Secondly, by showing that one cell division error can trigger a downstream storm of chromosome alterations with continuing cycles of ongoing change, our study reinforces the idea that early events in cancer are just bad luck associated with fairly common cell division errors.
What are the next steps for this research?
There are many aspects of the mechanisms that we describe that need to be better understood in molecular detail. We are excited to pursue an understanding of new “DNA footprints” of these mutational events that may have applications for cancer diagnostics. A major challenge would be to identify new ways to approach cancer therapeutics based on the current work. That will not be easy, but we and many others are excited about the possibility that the pulverization of chromosomes during chromothripsis or BFBs can stimulate innate immunity that may help eliminate tumor cells.
This work was funded by:
The Howard Hughes Medical Institute, the National Cancer Institute, the Ludwig Institute, the Lustgarten Foundation, and the G. Harold and Leila Y. Mathers Charitable Foundation.
