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.
Lab Members
Students and Alumni
Students
- René Toribio - Master's Student | CIRM Bridges Research Inter
- Juncong (Ashley) Shi, B.S. - Research Intern
- Nicholas Correnti - Research Intern
- Adelynne Yang - Research Intern
- Justin Buan - Volunteer
- Miles Dorff - Volunteer
- Andersen Yang - Volunteer
- Matthew Wong
- Rishabh Garg
Alumni
- Chun Li, Ph.D.
- Kenichi Kudo, Ph.D.
- Ben Mercier, B.S.
Our Publications
Careers
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