Mechanisms Underlying Genomic Amplification in Human Tumors
The Tanaka Laboratory is working on the mechanisms of genome instability, an enabling characteristic that drives unlimited proliferation and metastatic potential. Genomic amplification is a form of genome instability and is associated with abnormal chromosome structures. The part of the human genome harboring a cancer-driving gene often gains additional copies (amplification) that are associated with cancer progression and therapy resistance. The Tanaka Lab is investigating how genomic amplification arises and how we can prevent genomic amplification from occurring, leading to improved treatments for patients.
Recent work from the Tanaka Laboratory indicates that a mistake in DNA replication is a critical initiating event for genomic amplification. Accurate replication of DNA in the chromosomes is an essential process in cell proliferation. To replicate accurately, replication machinery has to travel a long distance, encountering many obstacles along the way that can impede replication machinery. The Tanaka Laboratory has shown that genomic amplification occurs frequently when DNA replication machinery is compromised. Tanaka Lab members have further shown that replication machinery stalls by colliding with transcription machinery, another essential cell-activity process within DNA. Stalled machinery can restart; however, restarted machinery is error-prone and can cause genomic amplification and abnormal chromosome structures.
With DNA replication as a target area of investigation, the Tanaka Laboratory is striving to find regions of the human genome that are prone to mistakes during replication and to develop an approach that selectively eliminates abnormal chromosome structures.
To do so, the Tanaka Lab uses an integrated approach to understand the mechanisms of genomic amplification. We employ genomic approaches to investigate DNA contents and gene expression in breast tumor tissues. Members of the Tanaka Lab use molecular and cytogenetic approaches to investigate the processes leading to genomic amplification in cell and mouse models.