Lu Zhang’s studies are at the cutting edge of cancer research. A fifth-year PhD student in Chemistry and Chemical biology, she investigates a class of enzymes—proteins that function as biological catalysts—and its application in cancer therapy. Zhang looks at enzyme modifications that are in clinical trial for treating breast cancers.
Zhang, who’s from Guangzhou, China, wanted to continue her studies in a completely different environment in a new city. The opportunity to follow her interest in cancer-related research that combines chemistry and biology is what brought her to Cornell. Before Cornell, she completed her undergraduate studies at Hong Kong Polytechnic University in chemical technology. She found her place at Cornell in the Hening Lin lab, Chemistry and Chemical Biology, where she can integrate her knowledge of cell biology and chemistry into her research.
“At Cornell, one of the reasons that I chose this lab was because of its interactive and collaborative environment,” says Zhang.
The Hening Lin Lab, Working across Fields
The Lin research group studies the application of enzymes and posttranslational protein modifications. Posttranslational protein modification is the alteration of proteins after synthesis to increase the functional diversity. Zhang describes the lab as a diverse group of researchers whose expertise ranges from chemistry and cell biology to animal studies. Instead of having just a narrow focus on protein structure and enzyme function, Zhang emphasizes that the diversity of expertise in the lab gives her an opportunity to learn many techniques across different fields.
“We start from chemistry—the structure of the enzymes and the reactions they catalyze. Then we go to cell biology. Sometimes we can also go to animal studies and work on animal models,” says Zhang.
Zhang uses organic chemistry to synthesize molecules, like probes to fish out enzyme substrates. To study the atomic structure of proteins, the lab uses x-ray crystallography, and mass spectrometry to monitor the reactions catalyzed by the protein catalysts.
Posttranslational Protein Modification and Cancer Treatment
“There are many types, hundreds, of posttranslational protein models. I specifically work on one type. I focus on a poorly understood protein posttranslational modification, ADP-ribosylation. In humans ADP-ribosylation is mainly catalyzed by a family of enzymes called poly(ADP-ribose) polymerases (PARPs). The goal of my project is to identify novel physiological substrates of PARPs in order to investigate the biological functions of ADP-ribosylation in cancer,” explains Zhang.
“We are trying to study PARPs for two reasons. First, very little is known about this modification. The second reason is that it is linked to cancer development.”
Proteins can be modified by different small molecules such an adenine diphosphate ribose (ADP-ribose) from nicotinamide adenine dinucleotide (NAD+). PARPs transfer ADP-ribose from NAD+ onto protein substrates. PARPs are involved in the regulation of biological processes, such as repairing DNA, remodeling chromatin, processing RNA, and regulating metabolism. Most importantly, PARP inhibitors are used in clinical trials to treat cancer.
Zhang elaborates, “In our lab, we develop a clickable analogue of NAD+ to better detect, purify, and identify the substrate proteins of PARPs. I concentrate on PARP1 and PARP7, which catalyze poly- and mono- ADP-ribosylation, respectively. Our work reveals how PARPs are involved in cellular metabolism and signaling. We’re also interested in the therapeutic potential of PARPs regulators.”
Zhang uses small molecule probes—powerful chemical tools—to detect and purify modified proteins such as ADP-ribosylated proteins. Probes identify the real targets of PARPs and elucidate its physiological function. Zhang first had to synthesize the probe. A challenging part of the research was that Zhang was unable to use antibodies—a common method of studying enzymes—to specifically recognize proteins in the cell. “So far there is no good antibody that recognizes PARP7 or its modification,” says Zhang. “We are trying to study PARPs for two reasons,” Zhang continues. “First, very little is known about this modification. The second reason is that it is linked to cancer development.”
Linking Lab Research with Clinical Data
Zhang plans to continue her research on cancer treatment and immunotherapy. Eventually, she wants work in a research lab affiliated with a hospital so that she can work on clinical data. “What happens in cells doesn’t really reflect what happens in human patients. Currently I’m working on cells, but I’m also interested in the effects of PARP inhibitors on humans,” says Zhang.
Through her work in the Lin lab, she has gained knowledge about the microenvironment of cancer cells and how they differ from normal cells. “In the future, this research can go in a lot of directions,” Zhang says. However, she holds to her interest in cancer biology and the importance of PARP inhibitors in treating cancer patients.
The Rewards of a New Experience
“One reason I chose Cornell is that it is very different from Southern China. I wanted to experience living in a foreign city, in a foreign country, with a whole new environment. So after living in a big busy city in Hong Kong, I really liked the slower-paced life in Ithaca. I get more time to interact with people and form stronger connections,” says Zhang.
In her spare time, Zhang likes going to local band performances around Ithaca. Her favorite spot on campus is the Fuertes Observatory on North campus. Zhang was in an astronomy club as an undergraduate, and she has continued the habit of going to the observatory. Zhang notes, “There are a lot of things to do here. I’m currently teaching myself how to play drums in one of the Lincoln Hall practice rooms.”