Prof. Dr. Polly Leilei Chen

Written by Dr. Julieta Rivosecchi

When Dr. Polly Leilei Chen reported for the first time in 2013 that “mutations” at the RNA level, in that case changes in RNA editing, of a cancer-associated gene could alter protein function to promote carcinogenesis (Chen et al. Nature Medicine, 2013), she did not imagine that ten years later she would be appointed RNA Society’s Asian Research Ambassador. Since her pivotal publication, Dr. Chen, currently the Assistant Head of the Department of Anatomy and Associate Director of the Cancer Science Institute of Singapore at the National University of Singapore, has continued to focus her research on RNA editing. RNA editing is a cellular process that uses enzymes such as members of the adenosine deaminase acting on RNA (ADARs) and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBECs) families to alter the nucleotide sequence of RNAs. Dr. Chen is a recognized expert in the fascinating RNA editing field. In particular, her lab explores the causes and functional consequences of RNA editing dysregulation in cancers. Moreover, she has substantially contributed to this area by developing novel therapies targeting these cancer-associated changes in RNA.

Dr. Chen took an atypical path to RNA biology. She started her career as a clinician but was quickly inspired by a colleague who sparked her scientific curiosity. She recalls, “I was a clinician working in a public hospital in China for 4 years and was first inspired by Dr. Yali Hu, a senior consultant in the Department of Obstetrics & Gynaecology, because she was not just focused on the diagnosis of prenatal abnormalities but was self-motivated to explore the causal factors leading to the abnormalities. Influenced by her dedication and curiosity, I realized that my real interest was to understand the molecular mechanism of human diseases such as cancer.” As a result, Dr. Chen decided to leave the hospital and pursue a PhD at the University of Hong Kong under Prof. Xin-Yuan Guan’s supervision. After completing her PhD, she moved to the Cancer Science Institute of Singapore to start her own research lab centered on the RNA biology of cancer.

Like most researchers, Dr. Chen’s career progression involved several relocations, each with its own challenges. During each relocation, her approach was to make sure that she took time to follow people’s interactions about work and life. She used her observations to help adapt to the cultural changes at her new location. She recognizes that the support she received from colleagues was also crucial for these transitions. She concludes: “My best decision was to give myself permission to take a bit more time when I was a newcomer. I needed to be open to the cultural differences that I faced and adapt to them when I was ready.”

The greatest challenge that Dr. Chen encountered in her career was “struggling to find a balance between ‘what you can do?’ and ‘what you should do?’”, regarding to committing to do too much service at the expense of her time for doing research. She finds that this is a recurring issue, and she is “still working on this”. Dr. Chen stresses how development activities outside of the lab have significantly impacted her training. She enrolled in two different programs: the EMBO Young Investigatorship Program and the Female Leadership Program developed by the National University of Singapore. She benefited from the EMBO Program for 4 years during the initial stages of her career as a PI. Through this the EMBO Program, she gained experience in organizing conferences, establishing collaborations, and attending workshops. As part of the Female Leadership Program, she had the opportunity to meet and interact with other women scientists and learn the leadership and management skills that helped her standing as an independent investigator. She explains: “This program has helped me gain confidence to make tough decisions, embrace challenges and redefine success and failure, which are all the important skillsets that we need to have in our academic life.”

As an adviser to graduate students, Dr. Chen strongly suggests that trainees “Stay focused, stay positive, and stay resilient. Completing a PhD is a long journey, and marks the beginning of your career, not just an additional degree or certificate you would like to collect to build your portfolio. Be careful and serious about the lab where you do your PhD research, by being careful when selecting the mentor or supervisor with whom you would like to work and learn from.” Moreover, from her personal experiences as a postdoc, she emphasizes that it was a combination of her stubbornness [to complete the project] together with great support from her supervisor that led her to discover the RNA editing world and envision herself as a scientist. “Prof.  Daniel G. Tenen at the Cancer Science Institute of Singapore, provided invaluable scientific advice and support, particularly in the early stage of my academic career, and he indeed inspired me to become a fearless scientist”, she explained.

My best advice to myself was to take a bit more time when I was a newcomer, to be open to the cultural differences that I faced and adapt to these when ready.

In the growing field of RNA editing in cancer, Dr. Chen is opening new avenues by investigating how RNA editing could induce immunosuppression in cancer. She is excited about the interplay between self-derived RNA species and the immune responses in cancer cells. In particular, she wants to deeply examine both how such RNA species originate and how they stimulate RNA sensing pathways. She approaches these basic research questions with a view towards the possible future applications: "I hope to be able to develop therapeutics which can intrinsically inflame pre-cancerous or cancerous cells. Doing this could be a new option to treat cancers as a way to supplement the immune checkpoint blockade therapy (ICBT) which currently only works for <20% cancer patients.”

Despite documented links between RNA editing and cancers, according to Dr. Chen her work still faces, obstacles and scepticism. She feels that definitively demonstrating that “ADAR enzymes and their editing substrates play a role in tumorigenesis” would be a key advance. However, the absence of genetic models to study the effects of ADAR enzymes during tumorigenesis coupled with the lack of animal models for a wide variety of cancer types, and the analysis of RNA editing in bulk tissues ignoring tumor heterogeneity and cell/tissue type specificity of RNA editing regulation, represent the main obstacles.  Nonetheless, she stresses the vast potential the field has to develop RNA editing-related therapies, not only for cancer. She details: “Researchers and industry are very excited to utilize the RNA editing machinery to correct G->A mutations occurring in genetic diseases such as cystic fibrosis, Rett syndrome, and others. In addition, many have put tremendous effort on modulating the expression/activity of RNA editing enzymes or editing level of their substrates using oligonucleotides or small molecule compounds to deactivate cancer-driven/promoting signalling pathways or induce tumors to trigger an immune response.”

Dr. Chen is very enthusiastic about her recent appointment by the RNA Society as one of the Asian RNA Research Ambassadors: “Through this opportunity, I hope to be able to communicate and interact with organisers of the RNA 2023 and leaders in the RNA field. This will broaden my view of RNA research internationally and develop further the local RNA community and young scientists, to work on this rapidly evolving area.”

 Dr. Chen, who enjoys the soothing experience of painting landscapes to calm her mind, is a big fan of double-stranded RNAs and antisense RNAs! Her favorite RNA journal paper is “Processing of Alu small RNAs by DICER/ADAR1 complexes and their RNAi targets”, from Yusuke Shiromoto, Masayuki Sakurai, Helen Qu, Andrew V. Kossenkov, and Kazuko Nishikura, 2020. Dr. Chen appreciates how the authors nicely showed an RNA editing-independent activity of a ADAR1 by demonstrating that ADAR1 can work together with DICER to generate functional endogenous small RNAs in somatic cells.

To know more about her lab and her research, do not hesitate to contact her through her lab’s Website and Twitter account: PLCLab_NUS @Pollych34650771.