2016 Recipient — Hui Shen, PhD

Hui Shen, PhD

An Epigenomic Approach to Delineate Cells of Origin in Early Tumorigenesis

Project Summary

The information to construct the cells of our body is encoded by our DNA, which is shared by almost all cells in the body. Despite having the same basic set of instructions, cells can vary dramatically in function, appearance, and composition, by using different parts of the genetic code. This process is guided by variable packaging and marking of the DNA, resulting in different utilization of parts of the genome in a process referred to as “epigenetics”. One of the most important epigenetic marks is a chemical change to DNA, called DNA methylation. In recent years, we have learned that cancer cells display extensive DNA methylation abnormalities, with some parts of the genome missing appropriate DNA methylation, and others gaining DNA methylation at abnormal sites in the DNA. I have contributed substantially to the characerization of DNA methylation abnormalities in gynecological cancers, participating in large consortia, such as The Cancer Genome Atlas, where I was the primary analyst in the epigenetic characterization of serous ovarian cancer, endometrial cancer, and uterine carcinosarcoma. Here I propose to use my expertise in DNA methylation characterization to identify the cell types that give rise to different kinds of ovarian cancer. Although DNA methylation undergoes marked change in cancer cells, many of the cell-type specific DNA methylation marks are still evident in the cancer cells, and can serve as a molecular memory of the originating cell type. We propose to use Whole Genome Bisulfite Sequencing to comprehensively characterize the DNA methylation profiles of purified populations of normal cells, as well as various benign and malignant ovarian tissues. Whole genome characterization of DNA methylation profiles has not yet been reported for ovarian cancers or normal cells related to ovarian cancer. Currently available DNA methylation data for these tissue or types only cover a small portion and a biased selection of the genome. For normal tissues only bulk ovaries or fallopian tubes have been used, where different cells are mixed together and target cells masked. We plan to make our data available to benefit the broader research community, after removal of uniquely identifying germline information.

Areas of Research:


Dr. Hui Shen joined Van Andel Research Institute’s Center for Epigenetics as an assistant professor in 2014. Prior to joining VARI, she completed her graduate studies at University of Southern California, where she received training in both cancer biology and biostatistics. She was a recipient of numerous fellowships there, including the Provost’s Ph.D. Fellowship; an NIH Cellular, Biochemical and Molecular Biology (CBM) Training Program Fellowship; and a Charles Heidelberger Memorial Predoctoral Fellowship. She received her undergraduate degree from Nanjing University, China.

Dr. Shen is a member of many national and international cancer consortia, including The Cancer Genome Atlas (TCGA), a consortium dedicated to better understanding the molecular basis of cancer through genomic analysis. Dr. Shen joined the TCGA team as a graduate student, and worked on understanding the epigenetic profiles of serous ovarian cancer. Her interest in ovarian cancer developed further when working on other types of female cancer, fueled by the discovery of a striking similarity between serous ovarian cancer and a subtype of breast cancer, as well as serous uterine cancer. Using epigenetic profiles of ovarian cancer as a cue, she identified the first subtype-specific and first clear-cell ovarian cancer germline susceptibility gene for ovarian cancer. Dr. Shen is particularly interested in cancer epigenome and its interaction with the genome, and using epigenetic profiles to understand cell of origin and both inter- and intra- tumor heterogeneity.

Finding Sparks, Fueling Motivation: Meet a Scientist

Photo: Dr. Hui Shen wearing black jacket and white shirt

Hui Shen, PhD, spoke of a particular moment that helped cement her commitment to ovarian cancer research. She was working on a complicated project that required a new genomics technology to work. So she and her team enlisted help from an expert. 

“This technologist made it all happen,” Hui explained. “We were jumping up and down with the data and I thanked her. It would not have been possible without her.”

While Hui felt completely indebted to this technologist for her contribution, the woman in turn thanked Hui for the opportunity to help ovarian cancer research. Ovarian cancer runs in the technologist’s family. 

“It’s moments like that,” Hui said, “that provide sparks.”

A career born in high school

Hui is an associate professor in Van Andel Institute’s Center for Epigenetics in Grand Rapids, Michigan. She grew up in China, and in high school was leaning toward chemistry. But her school encouraged her to participate in a national biology contest. She ended up winning first prize in the country and continued on this path.

Hui did her undergraduate studies in China, and then went to the University of Southern California for her PhD studying epigenetics. While at USC, she got involved with a national project run by the NCI (National Cancer Institute) called the Cancer Genome Atlas (TCGA). Ovarian cancer was one of the pilot projects, led by Dr. Doug Levine, a member of OCRA’s Scientific Advisory Committee. She recalled her first face-to-face meeting with all the collaborators where everyone shared their own discoveries with the ovarian cancer datasets. At the end of the long day with intense discussions, everyone was walking to dinner.

“Dr. Levine came running up and was talking to my advisor all the way to dinner, asking about the clinical implication of a molecular event that we studied,” Hui recalled. “He asked in such a pressing manner that I felt there were so many unmet needs. His passion was inspiring to me as well.”

Photo: Hui Shen PhD, smiling at outdoor restaurant

Curiosity, role models, patients

Hui remains fascinated by the number of unknowns that still exist in ovarian cancer research. These “interesting, unanswered questions,” especially surrounding the molecular mechanism, fuel her motivation. So do the other scientists.

“The ovarian cancer research community is so small and it’s full of really, really good people,” Hui said. “They truly care about the scientific research.”

When Hui moved from southern California to the Midwest, she fell in love with her colleagues’ shared drive; the way they respected their jobs, the way that everyone from the scientists to the administrative staff all work together and feel a sense of common purpose. “The level of synergy is quite different.”

And as Hui advances in her work, she’s meeting more and more patients. Seeing how they are impacted by the disease only increases her desire to help them.

“The patients are my heroes,” Hui said, reflecting on what it’s like to face a diagnosis that doesn’t always have a good prognosis. “Many of them, in a difficult position like that, give back by participating and consenting to be a part of ovarian cancer research.”

Epigenetics explained

A little biology for the laymen and women: our bodies have genes whose jobs are to keep our cells from becoming cancerous tumors. Sometimes these genes become mutated, such as the BRCA mutation, which means that the genetic sequence changes in such a way that these ‘tumor suppressor genes’ can no longer do their job.

Epigenetics is another mechanism by which a suppressor gene doesn’t work. Rather than a mutation of the strand of molecules in the gene sequence itself, epigenetics acts on top of the gene, turning off its ability to protect our cells from turning into cancer tumors. Epigenetics in and of itself isn’t a bad thing: turning on and off a gene’s function is what makes some of our cells grow into a brain, while other cells with the same DNA strands turn into hair, for example. But it’s a problem when it turns off a gene’s ability to fight off a tumor cell.

As science has developed a way to look at all of our genes at the same time (called a genome), it can also look at all of our epigenetics together as well. This is an epigenome, and the epigenome in ovarian cancer is the primary focus of Hui’s work. 

Dr. Hui Shen smiling while holding smiling baby

“My lab is not a traditional lab,” Hui said. “We have a lot of ‘dry space’ as opposed to ‘wet labs,’ and we develop computational tools to analyze the data that comes out of the wet labs.”

She’s also exploring, with a collaborator, how cells metastasize – what happens in that process and what promotes that process. Because, as Hui explained, “Ovarian cancer doesn’t kill people. It’s the metastasis that eventually kills the patient.”

Especially relevant advice

Hui would like people, especially women, to cut themselves some slack. She recognizes the physical toll the stress of balancing work and life can take on our bodies.

“Our mental and physical health should be our top priority,” she said. “Because as women, we tend to put other people – our family, our kids – ahead of us.”

She knows this advice may go against our maternal instincts, and flies in the face of many of our current realities. But she also believes that even mental stress can suppress our immune system. Something that this mother of two toddlers, who is balancing caring for children while working to cure cancer, is keenly attuned to.