Signe MacLennan is a PhD candidate in the Marra lab studying the role of extrachromosomal DNAs in mediating cancer treatment resistance. Extrachromosomal DNAs (ecDNAs) are a large circular species of DNA that drive cancer mainly by serving as vehicles for oncogenes and enhancers. Currently, Signe is profiling the genomic and epigenomic features of ecDNAs in cervical cancer using a variety of techniques including long-read whole-genome sequencing.

Q: What kind of research are you currently working on?

My research surrounds characterizing extrachromosomal DNAs (ecDNAs) with the aim to better understand their role in mediating cancer treatment resistance. Currently, the study I am working on is looking at the presence, structure, and regulation of ecDNAs in cervical cancer, which is a human papillomavirus (HPV)-driven cancer.  

For a bit of background: ecDNAs are a large, circular species of DNA that drive malignancy in some cancer types by serving as vehicles for oncogenes and enhancers. In cervical cancer, they can contain parts of the HPV genome in addition to human DNA (i.e. HPV-human hybrid ecDNAs) or exist with pieces of the human genome alone (i.e. human-only ecDNAs). Human-only ecDNAs likely form because of increased genomic instability, which is fairly common among cancers, whereas the HPV-human hybrid ecDNAs are believed to arise as a result of HPV integrating into the host genome creating double strand breaks, releasing the integrated segment, and forming a circular structure.

ecDNAs are quite prevalent in cervical cancer. For example, in our cohort of 118 advanced cervical cancer tumors from Uganda, we found that 30% have putative ecDNAs. We also found that these ecDNAs frequently contain genes annotated as oncogenes and that these oncogenes tend to be highly expressed. Additionally, HPV-human hybrid ecDNAs tend to be smaller and contain always contain the HPV oncogenes, E6 and E7, which are known drivers of cervical cancer.

Q: What led you to do this research, and more particularly, why did you choose to focus on cervical cancer?

In the Marra Lab, we have profiled this cervical cancer cohort before and another graduate student in the Marra Lab, Vanessa Porter, has been doing a lot of analyses on this cohort, specifically around HPV integration. She found evidence of HPV-human hybrid ecDNAs in this cohort. I was combing through these data, as well as the recent literature and found that the ecDNA field has reemerged in the last five to ten years. The earliest ecDNA data actually dates back to 1965, but now that we have all these improvements in sequencing technology and bioinformatics techniques, there are more opportunities to profile ecDNAs. Ultimately, it was a combination of what Vanessa found in her research and the literature on ecDNAs that led me to look more into ecDNAs in cervical cancer.

Q: What is the most exciting thing about your work?

I know it sounds corny, but the joy of being a researcher is that you get to learn and discover new things that no one has ever known before, which is really exciting. Even more exciting is that through this discovery, you may find something that pushes the field forward and could ultimately lead to improvements for patients, like identifying a drug target, or improving stratification of patients to existing therapies. 

Q: What is your long-term career goal?

I am not entirely sure, but I know I want to continue to be a researcher. Currently, my career goal is to be a staff scientist once I graduate so I can continue to do hands on research and work on projects in the field of cancer genomics.

Q: How does your team support you in your career journey?

I have a really supportive supervisor and lab mates. I can always ask questions and ask for feedback on things I have written or analyses I have performed. With my lab mates in particular, I can ask for advice on how to approach an analysis or what sort of bioinformatic tools to use. Having such a supportive lab environment helps with my career goals, because their guidance helps set me up for a successful degree, which will enable me to achieve what I want to do after graduating. 

Our lab explores a wide diversity of research questions. Although someone may not have encountered the exact same problem that you are working on, the diversity of the team offers such a wide range of knowledge and expertise that you can learn from and adapt to new situations.

Q: Name at least one person to send appreciation message? and why? (Not including your supervisors)

I would like to thank one of my undergraduate research supervisors, Dr. Zabrina Brumme from SFU. I did a USRA in her lab, right in the midst of the COVID-19 pandemic. She was really supportive of me, and I got a lot of valuable research experience in her lab. She has also been a big supporter of me through scholarship applications and I really appreciate her being such a strong advocate for me. I would say that she played a large role in me getting into the lab and program where I am now.