Researchers Battle Therapy-Resistant Cancer Cells by Identifying Aggressive Gene Enhancers

Zhijie “Jason” Liu, PhD

One of the biggest challenges in cancer treatment is therapy resistance.

Victor Jin, PhD (from left); Tim Huang, PhD, and Zhijie “Jason” Liu, PhD, are working together to map out the mechanisms of gene expression to battle therapy-resistant cancer cells.

That’s understandable when you consider all of our cells, even our cancer cells, have evolved with one purpose in mind: to survive and preserve themselves. As radiation and chemotherapy selectively kill cancer cells, any cancer cells that manage to survive treatment continue to divide and create more therapy-resistant cells.

New research at the Mays Cancer Center, home to UT Health San Antonio MD Anderson, reveals one reason breast cancer tumor cells are so notoriously resistant to treatment. They have an enhanced ability to quickly take on different forms in reaction to environmental stressors in a process known as “phenotypic plasticity.” The finding has important implications in the prospect of developing first-in-class therapies that target the mechanisms in which DNA is “read” by the cancer cell, rather than the cell’s DNA itself, making it more susceptible to therapy or, possibly, even reverting it back to a normal state.

Breast cancer is the leading cause of cancer mortality in Latina women in South Texas and is more often diagnosed in later and more aggressive stages in Latinas than in other populations. Cancer cells use this revved-up plasticity to change from a more stable state, that is more prone to destruction by chemo or radiation therapy, to a less stable transitional state which can result in a sub-population of more aggressive, therapy-resistant cells.

Can this supercharged plasticity be reversed by altering the cell’s environment? Epigenetics may hold the key. Humans are the product of both nature and nurture. Genetics accounts for our cellular instructions and predetermines a cell’s specialization to become a skin cell, hair cell or blood cell, for example, but epigenetics accounts for the cumulative impact of our environment on those genes, affecting which genes are turned on or off to best cope with that environment. How we eat, sleep, and exercise, for example, is all expressed in our body through epigenetics.

Zhijie “Jason” Liu, PhD, an investigator with the Mays Cancer Center, is senior author of the new research on phenotypic plasticity and cancer published in May 2020 in Nature Cell Biology. His team studied the epigenetic signals that enable breast tumor cells to quickly change phenotype to evade treatment. While the study focused on breast cancer cells, the same theory applies to other treatment-resistant cancers such as lung and prostate cancer, says Dr. Liu, a CPRIT Scholar in Cancer Research and an assistant professor of molecular medicine at the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio.

“Cancer cells are very dynamic and heterogenous and can easily change to adapt to their environment. What are the major drivers that control this environment-responsive landscape in cells? We have to understand the cancer adjustment strategies to the environment and identify those drivers. Tumor cells are very smart and try to hijack many normal cell processes and then try to adapt them to their advantage,” he explains.

Dr. Liu’s research is funded by the Cancer Prevention and Research Institute of Texas, the V Foundation, the Max and Minnie Tomerlin Voelcker Fund, Susan G. Komen, the National Cancer Institute, the National Institute of General Medical Sciences, the Mary Kay Foundation, and The University of Texas System.

Gene networks in cancer cells react to various signals in their environment. Those signals can include hormones, inflammation, and metabolism, and they play an important role in regulating how genes are read under normal conditions. But the network can also dysregulate gene expression in a disease environment. This is of particular interest to Dr. Liu because studies show epigenetic signaling is reversible, opening up a whole new perspective on battling diseases such as cancer.

The regulation of gene expression occurs at the molecular level by the binding of proteins to certain regions of the DNA (so-called enhancer regions in our genome) to increase the likelihood a particular gene will be turned on or off. Dr. Liu’s team identified the specific proteins, called “enhancer reprogramming drivers,” at work in the breast cancer tumor cells that switched on the cancer cells’ ability to become more plastic and unstable in an effort to evade therapies trying to kill them.

The next step is targeting those drivers with drugs to essentially reprogram the way the cancer cell reads its genetic instructions and reverse it back from a plastic cell to a more stable cell that is more susceptible to therapy or possibly even a benign version of its former self.

Understanding the entire gene network is a huge challenge considering humans have between 20,000 and 25,000 genes and more than 300,000 enhancers in human genome that can impact how those genes are expressed. Yet, in theory, if gene functions can be mapped, along with their associated enhancers, you would get a big picture of what is happening in disease pathology and how you might reverse it. A huge undertaking, but one that Dr. Liu believes would be well worth the effort.

“I have to have the big picture of enhancers and the protein drivers on them first, otherwise I don’t know what to do next,” Dr. Liu says. “Cancer is not just one mutation; there is so much more going on. We need to see the big picture and then determine the functional definition for each unit at the molecular level. In the future, this will allow us to personalize the treatment for each patient based on his or her own genome and epigenome.”

New technology in deep sequencing will help bring the big picture into focus. “We no longer study genes one by one,” Dr. Liu explains. “We use both molecular biology and deep sequencing technologies in both mouse models and human models for breast cancer to start to understand the enhancer reprogramming dynamics and the drivers that control these reprogramming events, along with other epigenetic markers, to create a kind of map.” Not like two-dimensional maps of old, he likens it to an interactive Google® map that shows you not only the detailed layout, but the functions of various landmarks and businesses along the way, and the best route to take for a certain result.

Tim Huang, PhD

Mapping out the mechanisms of gene expression underlying cancer plasticity is already underway. UT Health teamed up with Duke University to form the San Antonio-Duke University Research Center for Cancer Systems Biology (SA-Duke RCCSB) which will help with preliminary work to uncover gene functions and map out the vast regulatory network. Two other senior leaders Tim Huang, PhD, and Victor Jin, PhD, professors of molecular medicine and two collaborators on Dr. Liu’s study, are leading the 21-member team to develop computational and genomic approaches to identify the elements of these networks using both lab work and cutting-edge sequencing techniques.

“Dr. Liu is an important player in our SA-Duke RCCSB center, and he brought a lot of new technologies to our Mays Cancer Center,”
Dr. Huang explains.

“Dr. Liu’s work in this area is very impressive,” Dr. Jin says. Of course, mapping out the interaction of the genes and their enhancers, he adds, will take some time beyond SA-Duke RCCSB’s current five-year grant.

The task is daunting, but not impossible. “As new technology comes faster and faster, we will get closer and closer,” Dr. Liu says. After all, sequencing of the human genome and epigenome, at one time thought impossible, now can be done in just days.


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