Li Lab
Research Lab Overview
Inflammation, Oxidative Stress and Mutational Signatures as Biomarkers of Cancer Risk
Cancer susceptibility results from the complex interplay of both inherited and acquired genetic mutations as well as environmental risk factors. Much of what we know about the natural history of human cancers are focused on the carcinogenic or cancer initiation events such as driver mutations. In contrast, limited attention has been paid to cancer promotion and the impact of chronic inflammation to such risk factors on cancer progression. Chronic exposures leading to an inflammatory response include obesity, high fat diet, increased oxidative stress and repetitive injury, but also in resistant/persistent tumors after radiation therapy and chemotherapy. Identifying the factors that play a critical role in cancer promotion and the genomic hallmark of such processes can provide novel therapeutic angles in cancer control and prevention by identifying patients with early or pre-cancerous lesions who are at high risk for progressive or metastatic disease.
In addition, defining the molecular signatures of promotional mechanisms can be used to develop algorithms that predict treatment response and identify new therapeutic avenues. For example, central to the therapeutic mechanism of radiotherapy is the generation of reactive oxygen species (ROS), which in turn causes DNA damage and inflammation. However, while some cancer types are known to be more radioresistant, radiosensitivity for any given tumor is not predictable. Identifying a somatic mutation signature for oxidative stress response can help select for those patients who may benefit from synergistic therapeutics such as radio-mimetics, checkpoint inhibitors, or alternatively, ROS-promoting agents that can accentuate the effect of radiotherapy. The focus of my laboratory is on understanding the role of ROS both in cancer risk and treatment response in genitourinary and colorectal cancers.
Epigenomic Signatures of Cancer Origins and Impact of Tissue Development
My lab is also interested in the complex interplay of the genetic and environmental causes of cancer susceptibility, which is captured by differences at the level of gene expression but also by examining patterns of differences in mutations in the non-coding regions of the genome or epigenome. There is limited knowledge of whether a specific type of mutagen (e.g., ROS-generating) would have distinct physical patterns (epigenomic signature in a sense). This is important because if there is bias towards regulatory regions, this may impact the functional relevance even if they are non-coding. We found that in tumors from animals with either genetic predisposition to high BMI or fed with high fat/high calorie diets, somatic mutations map more frequently to transcriptional regulatory regions known as CCCTC-binding factor (CTCF) binding sites. Furthermore, others have reported that in obese F1 generation mice exposed to bisphenol A, there was widespread increase in chromatin accessibility at binding sites for CTCF and other transcription factors accompanied by alterations in 3D organization. This is consistent with our preliminary data showing increased accumulation of somatic mutations at CTCF binding sites. In this aim we will use an in vitro assay to evaluate the impact of growth stimulation, nutrient deprivation and cytokine exposure on ROS mutation accumulation. This model will allow us to test the hypothesis that ROS mutations preferentially accumulate at CTCF binding sites and is modulated in different nutrient and growth conditions.
We also have shown that cells in different stages of differentiation and embryogenesis may be differentially susceptible to mutagenesis and likely carcinogenesis. However existing approaches to examining the topography of mutational signature approaches are focused on examining whether genomic changes assigned to a specific mutational signature are mapping proximal to specific functional loci in the genome, such as CTCF binding sites. We plan to test the hypothesis using a novel molecular and computational model that such a unique topography exists to modulate which cells at what developmental timepoint may be more susceptible to mutagenic events.
Mitigating Radiation Treatment Toxicity Through the Metabolism
Equally important is our interest in mitigating the side effects of radiation therapy. One of the most important implications that could be derived from this work is how modulation of the effect of ROS could be clinically meaningful. We have previously shown that ROS mediated DNA damage is present in a majority of gamma-irradiated tumors induced in animals and it is well-established that ROS acts as a double-edged sword in the treatment of cancer, both simultaneously driving the cause of tumor killing and mediating normal tissue toxicity. Multiple preclinical studies provide evidence supporting the benefit of fasting or caloric restriction during RT as a way to mitigate toxicity or risk of secondary malignancy. Recent work by Dr. Tanya Dorff at COH shows that peri-infusion fasting-mimic diet in patients receiving platinum doublet chemotherapy can significantly reduce DNA damage in normal tissues and possibly improve treatment efficacy. Fasting appears to be safe and well tolerated, as also demonstrated in a number of other studies using both fasting and caloric restriction approaches. Importantly, these studies have shown no evidence of detriment to tumor kill or disease control with the use of fasting or caloric restriction protocols; in fact, several studies have reported improved treatment efficacy.
There is arguably even strong impetus to consider the benefits of dietary intervention in the context of RT, where oxidative stress is a primary driver of DNA damage. In contrast to chemotherapy, which is delivered in many cases in a single or multi-day infusion regimen over several cycles, RT is typically delivered daily for 5 days a week (most typically), over a number of consecutive weeks. Implementing a complete fast or even a fasting mimic diet for such a duration is unreasonable and impractical. More importantly, normal tissue healing requires energy and nutrient intake. Optimizing normal cellular repair requires careful consideration of how to reduce the impact of metabolically produced ROS while balancing the difficulty imposed on cancer patients during rigorous cancer treatment.
Toward this end, we are launching a Phase 2 randomized study to evaluate the potential benefit of intermittent fasting in patients undergoing pelvic radiation therapy for prostate, cervical and rectal cancers. Since radiation causes damage to cells by inducing reactive oxygen species and normal cells have capacity for repair for such damage whereas tumor cells lack normal repair capacities, fasting could help mitigate the accumulation of ROS mediated DNA damage in normal tissues and offer a protective mechanism for normal tissue during radiotherapy. We are evaluating the benefit of this approach clinically but also through the development and implementation of sensitive, non/minimally invasive biomarkers in blood, urine and stool.
Yun Rose Li, M.D., Ph.D., is an assistant clinical professor and physician scientist in the Department of Radiation Oncology and Department of Cancer Genetics and Epigenetic at City of Hope® Cancer Center Duarte, California. She also holds a joint appointment in the Quantitative Medicine and Systems Biology at the Translational Genomics Research (TGen) Institute in Phoenix.
Ziyi (Zoey) Huang, M.D. went to medical school at Shanghai Jiao Tong University and worked for the China office of the University of Nebraska Medical Center as the office manager for a couple of years after graduation.
After being trained to become a healthcare provider in medical school and being the bridge between society and medical care providers, Ziyi found herself enjoying it more when she was able to provide care to the patients directly. In sight of this, she came to the United States to continue her path of becoming a doctor.
Chun Li had his medical education and academic research training in Medical School of Soochow University in China in the 1980s of the 20th century. In 1991, he was awarded the McAlester Research Fellowship from USC, which brought him to Los Angeles from his hometown, SuZhou, a beautiful and historical city in eastern China. It is known as the “Venice of the East”.
He has a long-standing interest in exploring the cancer etiology and treatment. As a senior medical researcher, he has worked in cancer research area more than 30 years. He has much experience in cell, exosome, DNA, RNA, protein, and mouse model level and clinical medicine. He has been working at City of Hope since 1997. He values the friendship and is an easy and flexible person. He also likes hiking and watching movies. He enjoys his time with his family and eating Asian food.
Kenichi Kudo, Ph.D. received a Ph.D. in radiation biology and physics field from Hiroshima University in Japan in 2016. Based on the cohort study of radiation-induced cancer in A-bomb survivors by the Radiation Effects Research Foundation (RERF) in Hiroshima, it has been found that the incidence of carcinogenesis in human mammary gland is very high (Preston et al. 2007), so he has been studying radiation effects on human and rat mammary glands and the mechanisms of radiation-induced breast cancer development at the National Institute of Radiological Sciences (NIRS) until Mar 2020. His interest in radiation effects on epithelial tissues started then. After there, he continued his research and pressed some articles at Fukushima Medical University for about 3 years, and for the reason he needed NGS analysis techniques and overseas careers, he decided to join in the Rose Li’s lab which has been targeting the radiation, NGS, and the prostate gland. He's very interested in the radio-resistance of cancerous cells to resolve the problem of radiation therapy. He's very excited to join in this lab.
Kavya Achanta, Ph.D. was inspired to pursue a career as a molecular biologist after attending a lecture as an undergraduate on cell cycle regulation, as she was fascinated by the intricate regulation of cell division and replication. She moved to Lund University, Sweden, from India for her Master's program in Molecular Biology. During her Master's thesis, she was mentored by Claus Storgaard Sørensen at the University of Copenhagen, Denmark. She developed excellent molecular biology wet lab skills and gained a strong understanding of regulation of genomic stability in mammalian cells and how impairments of these mechanisms cause diseases such as cancer and neurological disorders.
During her Ph.D., she was mentored by Dr. Vilhem Bohr and Dr. Mansour Akbari at the University of Copenhagen, Denmark for her thesis on the "Molecular mechanisms of DNA repair deficiency and mitochondrial homeostasis impairment in neurological diseases." She also had the opportunity to visit the National Institute on Aging in the United States to learn about using C. elegans as a model organism in studying mitochondrial dysfunction in age-related neurodegenerative diseases. Subsequently, Kavya continued her research efforts during her research fellowship at Lund University, Sweden, for 23 months under the mentorship of Dr. Isabella Artner. Her work focused on: 1) Understanding the key role of transcription factors MafA and MafB in beta cell differentiation, pancreas development, and pancreatic cancer. 2) Gaining experience in computational analysis of single-cell RNA sequencing and bulk-RNA sequencing.
In November 2023, she joined the City of Hope as a post-doctoral fellow in Dr. Yun Rose Li's lab. Dr. Li has a unique background and mentoring philosophy and has agreed to support her goal of combining advanced training in cell and molecular biology with integrative genomics and computational biology. Furthermore, her experience as a clinician and practicing radiation oncologist provides Kavya opportunities to work on proximal-to-patient translational research projects and address important scientific questions that are directly relevant to human health.
Qianhua Feng, M.S. graduated from University of Southern California School of Pharmacy. She learned basic biochemical and molecular biology techniques including MAOA catalytic assay, cell viability MTT assay, metabolic flux Seahorse bioanalyzer, western blots, genotyping from master. She's involved in several projects of novel anti-cancer drug discovery (MAOA inhibitor-NMI) in glioma, colon cancer, and non-small cell lung cancer. She would like to explore the bioinformatics field and want to combine previous knowledges with bioinformatics to understand unclear factors in human cancers.
Tariq Abuali, B.S. attended University of California Riverside which is where he received his bachelor's degree in biology and worked an intern at a neurofeedback clinic for addiction patients, was able to gain a lot of patient experience and from there worked at a PT clinic gaining more experience in other medical fields. He's always wanted to be in healthcare because he wanted to be a difference in the community that he served in regarding care. From those experience cancer being one of the areas, he has always wanted to be a part of lead me to City of Hope where he's able to do in the best possible way.
Growing up in the area, Ben Mercier, B.S. has been on at least two field trips in grade school to City of Hope, so the has always appreciated the opportunity to work at City of Hope. He graduated from the University of California, San Diego in June 2021 with a Bachelor of Science in Molecular and Cell Biology and wants to eventually attend medical school.
As an undergraduate, Leslie Wenning, D.V.M., M.S.-L.A.M. majored in psychology and obtained a New York State Elementary Teaching Certificate from Vassar College (Poughkeepsie, NY). She loved studying the human mind and genuinely enjoyed teaching elementary school children in both the US and UK. She also enjoyed working with animals while doing undergraduate research. Thus, after graduation, She wanted to enter a field that combined her passions for psychology, education, and research. As either a physician or veterinarian, she could be a health educator and scientist, as well as a source of emotional support, to either patients or patient’s owners. She was torn between applying to medical versus veterinary school, but her father’s passing during that time personally motivated me to become a physician. However, during her third year of medical school, she realized that she missed working with animals. As a veterinarian, not only would she get to work with animals and conduct research, but she would get to use her psychology and education skills with their owners. Subsequently, she left medical school and was accepted to veterinary school. Given her background in human medicine, she was immediately drawn to the field of laboratory animal medicine due to the emphasis on comparative medicine between humans and animals. More importantly, she has always believed that laboratory animals deserve access to enrichment, health, and ethical research protocols. Finally, she had found her calling; and in May 2022, she graduated from Tufts University Cummings School of Veterinary Medicine (North Grafton, MA) with a Doctor in Veterinary Medicine (DVM) and Master’s in Laboratory Animal Medicine (MS-LAM). Currently, she is a Resident Veterinarian, Laboratory Animal Fellow, and PhD Candidate in Biological Sciences at City of Hope (Duarte, CA). Human and animal health are interconnected, and she looks forward to working on preclinical animal models in the Li Lab to provide a better prognosis for both human and animal patients with cancer.
Maria Isabel Chosco earned her bachelor's degree in cell and molecular biology from California State University Northridge (CSUN). Her journey into research began with microbiology, evolving into a comprehensive exploration of genomics and bioinformatics. Currently, she is pursuing a PhD in Dr. Li’s lab, where her focus lies in delineating epigenetic regions and mutational signatures associated with obesity-related colorectal cancer and prostate cancer.
Juncong (Ashley) Shi, B.S. recently graduated from University of California San Diego and majored in Cognitive Science with specialization in machine learning and neural computation. She aspires to transform biological data into assets that help humans understand themselves and enhance public health.
Nicholas Correnti is currently a senior at Occidental College. He is a biochemistry major and an economics minor. He plans on applying for medical school next year and aspire to become a physician.
The internship at Dr. Li’s lab has been his first experience doing research and he has wanted to learn about the process behind it and how it can be applied in a clinical setting. His time here has shown me how important our work is and how we are using our newfound knowledge to improve the lives of our patients.
Alicia Rodriguez is majoring in biology with a minor in neuroscience at Occidental College in Los Angeles, California. After graduation she plans to go to medical school and specialize in neurology. As someone who has suffered from three concussions in my life, she is eager to help treat patients with neurological disorders. She hopes to get involved with and help under resourced communities be able to receive access to healthcare. She is currently working with a non-profit organization, Global Brigades, as a chapter leader to help bring a preventative and primary health clinic to communities in Guatemala.
Cancer is a ubiquitous disease that has affected two significant people in my life. Being able to participate in research that strives to help cancer patients feels extremely rewarding because though she is not a physician yet, she is still able to contribute in helping this population.
Matthew Wong is a senior in high school with plans to major in molecular biology. His research interest began after he took a biology class at his school. Getting to talk with one of the professors who taught a stem cell module there motivated him to pursue an internship during the summer at UCLA. After my internship ended, he still had a desire to continue doing research which leads to where he am today in Dr. Li’s lab.
In Dr. Li’s lab, his main focus has been learning different assays/experiments. Recently, he has been repeating a prior project that investigated the potential benefits of fasting for patients undergoing radiation therapy. By limiting cancer's access to energy through fasting, we aim to disrupt the mechanisms crucial for repair, ultimately seeking to enhance the efficacy of radiation therapy.
Rishabh Garg is a Junior at North Hollywood Highly Gifted Magnet and is working towards a career involving pediatric care and oncology research. Currently an intern at CSU Northridge, Rishabh works weekly with various agarose and cell migration assays. Active participation in various community activities, especially hospital volunteering, brings Rishabh immense satisfaction. Rishabh volunteers at Cedar Sinai weekly and has the privilege of assisting as a volunteer at Children’s Hospital Los Angeles for the entire 2022 summer.
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Career
Our Research and Training Philosophy (much of this is credited to Daniel Kahneman):
The scientific questions we’re exploring are big and complex; answering them requires the collaboration of many people with different perspectives, backgrounds and skill sets. We stress the importance of discussing ideas and scientific problems with others inside and outside of the lab. Most importantly, we believe it’s essential that everyone feels comfortable asking for help. Sharing knowledge, insights and expertise moves science forward. We work to make sure that every lab member can comfortably and respectfully question others’ hypotheses and conclusions. Just as experiments and bench work are essential for driving research forward, an attitude of continuous curiosity is crucial for developing scientific researchers. Our main priority is that students and postdocs learn how to think about difficult scientific problems.
We believe that mentorship is fundamental to science. Though institutional hierarchy dictates a set of mentor-mentee relationships, we also foster mentorship from peers and collaborators. Daily communication allows senior members of the group to educate and advise newer members, and we encourage newer members to seek guidance during their development as scientists. Each lab member will have their own career goals and aspirations. To this end, the lab aims to encourage and assist members in attaining the skills, connections, experiences and confidence they need to pursue the career of their choice.
We prioritize the physical, mental and emotional well-being of every lab member. We recognize that people have different needs and unique personal circumstances outside of the lab, and thus will have different limits. We also acknowledge how easily graduate students, postdocs and lab staff can feel socially isolated. We work to mitigate feelings of isolation by looking out for one another and creating an environment where personal wellness is valued above all. Graduate school and postdoc positions are stressful and can be overwhelming. Undue stress and anxiety, in particular the chronic low-level stress that can accompany an unsupportive atmosphere, are not conducive to developing as scientists or as people. We strive to keep our lab environment challenging but supportive, with reasonable expectations and open communication. To build camaraderie within the group, we host activities outside of research such as game nights, hikes, swimming, and group dinners. We hope you will join us in becoming a part of this community of people passionate about learning, creating and most of all – helping one another grow.
Contact Information
34.1291938, -117.9728148
Duarte, CA 91010