Jindan Yu, MD, PhD, professor of Medicine in the Division of Hematology and Oncology and of Biochemistry and Molecular Genetics, usesintegrative genomic and bioinformatics approaches to shed light on the molecular mechanisms underlying prostate cancer progression, findings which could inform the development of novel therapeutics.
Beyond her work in the laboratory, Yu is also the assistant director of education & training and co-leader of the Translational Bridge Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
What are your research interests?
My research interests are to understand genetic and epigenetic regulations of prostate cancer by utilizing cancer genomics, bioinformatics and big data analysis approaches. We are fascinated by contemporary technologies to study gene regulation at genome-wide, systems levels on one end, and at single-cell, base-pair resolution on the other.
Our current research has two major focuses. One is on understanding how the androgen receptor — a hormonal transcription factor at the center of prostate cancer initiation and progression — works in concert with a key set of co-regulators such as FOXA1, GATA2, HOXB13 and mediator proteins. We then examine how disrupted expression of these genes reprograms the androgen receptor and promotes resistance to prostate cancer treatment. Another focus of the laboratory is on epigenetic regulation of prostate cancer with special interest on the polycomb group protein EZH2, and on DNA methylation and de-methylation enzymes, such as TET1.
What is the ultimate goal of your research?
Prostate cancer is a leading cause of cancer-related death in American men. There are two overarching challenges in prostate cancer research today: 1) to distinguish indolent prostate cancer from aggressive ones to avoid overtreatment and 2) to effectively treat late-stage castration-resistant metastatic prostate cancer to prolong patient life. Through mechanistic studies described above, we aim to reveal novel cancer biomarkers and therapeutic targets that can inform the development of new drugs and treatment regimens. The ultimate purpose of my laboratory is to benefit prostate cancer patients.
Currently, we are developing a blood-based cell-free DNA epigenetic signature for newly diagnosed patients to distinguish those with clinically significant prostate cancer in need of treatment from low-risk patients who could be assigned active surveillance. We are also developing new drugs targeting EZH2 and chemokine receptor CXCR7, and promoting several combinatorial drug treatment regimens in clinical trials.
Where have you recently published papers?
We have three recent publications: In November 2018, we published a study of TRIM28 in prostate cancer in Nature Communications. In a paper published in Cell Reports, we reported a previously uncharacterized role of EZH2 as a transcriptional activator, which does not require its methyltransferase function and is independent of other polycomb subunits. This role of EZH2 is particularly important in prostate cancer as androgen receptor (AR) is a primary target. Our study suggests the insufficiency of enzymatic inhibitors to fully block EZH2 function and the necessity of combining with AR-targeted therapies. In a paper published in the Journal of Clinical Investigation in December 2018, we reported that FOXA1 loss in late-stage prostate cancer leads to activation of the TGF-beta pathway. Preclinical data showed that TGF-beta pathway inhibitors greatly reduced cancer growth and metastasis, directly supporting a clinical trial to test the efficacy of TGF-beta receptor inhibitor galuniertib in combination with standard AR-targeted therapy in castration-resistant prostate cancer. This project is supported by Northwestern’s prostate cancer SPORE.
What types of collaborations are you engaged in across campus (and beyond)?
The research environment at Feinberg and the Lurie Cancer Center, with the aid of the prostate cancer SPORE, is outstanding and has cultivated a number of collaborations. We work very closely with Northwestern prostate cancer SPORE investigators, including Drs. William Catalona, Maha Hussain, Sarki Abdulkadir, Ximing Yang, Alicia Morgans, David VanderWeele, Bin Zhang and Denise Scholtens, on multiple translational projects. We are also collaborating with Drs. Massimo Cristofanilli, Edward Schaeffer, Adam Murphy, Qi Cao, Debu Chakravartiand Jian-jun Wei on campus. Through the SPORE, I’ve also formed collaboration with many investigators outside of Northwestern University. For our drug development projects, we have been mainly collaborating with Dr. Gary Schiltz on the Evanston campus.
How is your research funded?
My research was initially funded by a K99/R00 pathway to independence award and an R01 from the NIH, a new investigator award from the Department of Defense (DOD), and a Research Scholar Award from the American Cancer Society. My research program is currently funded by a new R01 to study the role of NF90 proteins in prostate cancer, a project in SPORE to perform translational research targeting FOXA1 downstream pathways in late-stage prostate cancer, and a Prostate Cancer Foundation Challenge Award to target chemokine signaling and MAPK/ERK pathway. My laboratory is also currently supported by three DOD grants, including an Impact Award to develop novel approaches to target EZH2 in castration-resistant prostate cancer. Nearly half of our research funding supports translational cancer research, while the other half is for basic science research.
Who makes up your research team and what role does each individual play in your research?
My laboratory team can be divided into two major groups: dry lab and wet lab, which are supervised by Drs. Jonathan Zhao and Will Fong, respectively. Dr. Zhao, who has been working with me since 2009, establishes and maintains the infrastructure and pipelines for bioinformatics analysis and has performed bioinformatics, integrative and big data analysis for almost every one of our lab projects. Dr. Fong, who joined my laboratory in 2013, is currently the lab manager of the wet lab. Zhao and Fong have been instrumental to the research program in my laboratory. Other important members of the Yu laboratory include postdoctoral fellows Drs. Nathan Damaschke, Xiaodong Lu, Song Tan, and Guihua Zeng; graduate students Galina Gritsina and Kevin Park; and lab technician Rakshitha Jagadish.