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  1. Neff Newitt, Valerie

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Huanhuan Joyce Chen, PhD, PharmD, took a long and complicated path to her professional home at University of Chicago where the assistant professor holds joint positions in the Pritzker School of Molecular Engineering and the Ben May Department for Cancer Research. Her lab seeks to determine how various cancers initiate and progress using human cell origin cancer models in hopes of eventually designing novel strategies to diagnose, categorize, and treat these cancers.

  
Lung cancer. Lung ca... - Click to enlarge in new windowLung cancer. Lung cancer

Chen came to her current professional home from Wenzhou, a small city in China, where she was born to a military officer father and an accountant mother. "My father always told me to go as high in education as I could," said Chen, who clearly heeded his advice. "I received my PharmD degree from Zhejiang University, one of the top universities in China."

 

While an undergraduate student, she started a cancer research project to examine the anti-tumor effects of artemisinin derivatives, a famous anti-malaria Chinese herbal medicine, and the role they play in cancer.

  
Huanhuan Joyce Chen,... - Click to enlarge in new windowHuanhuan Joyce Chen, PhD, PharmD. Huanhuan Joyce Chen, PhD, PharmD

"The hypothesis was [that] artemisinin derivatives may play an important role in blocking angiogenesis in cancer," Chen told Oncology Times. "So I did individual studies and found that, yes, artemisinin derivatives are very good at blocking angiogenesis. Eventually, I was able to publish several articles in English journals (one such example: Pharmacol Res 2003; doi: 10.1016/s1043-6618(03)00107-5). That was extremely encouraging, since this was my very first research project."

 

Not only was the research a success, but writing and publishing in English was quite a triumph for the young woman who could not yet speak English with fluency.

 

Following graduation, Chen worked as a hospital pharmacist for 3 years while trying to decide if she should press on as a clinical pharmacist, become an oncologist, or dive into creative research. Realizing she had a true passion for research, she left China for the U.S. "because the U.S. has the most advanced science and technologies in the world," she declared. "I went as a visiting scientist to the Albert Einstein College of Medicine in New York City. I forced myself to communicate in [spoken] English. That helped me to master the language."

 

Her journey to America helped her further define her career path. "I realized, in order to treat cancer better, we need a comprehensive understanding of the basic biology of cancer and how a therapeutic can take effect. I knew I needed a PhD training to understand the mechanisms," said Chen, who was accepted into a doctoral program at Cornell University.

 

Here, Chen's first mentor, Steven Lipkin, MD, PhD, pulled her deeper into cancer research in his lab, which used humanized mouse models to explore and decode the cell mechanism behind colorectal cancer metastasis. Her contributions in the lab resulted in more journal publications for the budding researcher and a basic understanding (J Clin Invest 2012; https://www.jci.org/articles/view/62110). "Cancer is very complicated, and while mouse models are powerful, we really need interdisciplinary knowledge to develop better models, better tools, into the field of traditional cancer research," Chen noted.

 

Harnessing Engineering Concepts

It was at this time that Chen met bioengineering pioneer Michael Shuler, PhD, who suggested she employ "engineering research logic and engineering tools to help decode the mechanisms of cancer and develop therapies," Chen recalled. "So I spent the last 2 years of my PhD program in his labs and developed artificial colorectal cancer models..." which were detailed in yet another publication (Nat Biotechnol 2016; doi: 10.1038/nbt.3586).

 

According to the abstract, "refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia."

 

The research team identified 38 candidate invasion-driver genes, 17 of which were previously implicated in colorectal cancer progression. "Six invasion-driver genes that had not been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon," noted Chen, who was lead author. "The results demonstrate the utility of our organotypic model for studying cancer biology. This artificial cancer model gives us a tremendous opportunity to observe how cancer cells behave throughout disease progression in a petri dish."

 

After receiving her PhD, Chen re-evaluated her knowledge foundation. "I realized, again, that I needed a deeper training on cancer biology, because I drifted from biology to engineering; it was time for me to go back to biology to be able to identify and answer deeper questions." Toward that end, she did post-doc training in the cancer biology lab of Harold Varmus, MD, where her engineering experience bolstered his existing biology emphasis.

 

"He was interested in using human origin cells to study cancer disease," Chen noted. "In the cancer research field, most knowledge about cancer mechanism is derived from animal models; there have been no robust cancer models actually developed from human cells from day one of the disease."

 

She said when researchers are able to culture primary human cells, they cannot be grown robustly; they typically change biological behavior, become different to the native ones, or just die. "The expansion of primary human cell is limited, so you cannot use those cells for in-depth studies."

 

Emergence of iPS

Japanese researcher Shinya Yamanaka, MD, PhD, won the Nobel Prize in Physiology or Medicine (jointly with developmental biologist Sir John B. Gurdon, FRS FMedSci MAE) in 2012 for discovering that mature, specialized cells "can be reprogrammed to become immature cells capable of developing into all tissues of the body," according to the Nobel Prize Outreach. "The findings revolutionized understanding of how cells and organisms develop."

 

The online resource explained, "Yamanaka studied genes that are important for stem cell function. When he transferred four such genes into cells taken from the skin, they were reprogrammed into pluripotent stem cells that could develop into all cell types of an adult mouse. He named these cells induced pluripotent stem (iPS) cells."

 

"My mentor, [Harold Varmus] suggested I might be able to model cancer disease using iPS," recalled Chen, "so I went to the Hans-Willem Snoeck lab at Columbia University to learn the advanced technology of differentiating human pluripotent stem cells (hPSC) into specific lineages."

 

Chen brought this knowledge to bear on cancer research back at Weill Cornell Medicine. She started differentiating hPSC cells into various cell types in lung epithelium, including a cell origin for lung cancer. First, she had to differentiate the pluripotent stem cells into the correct type of normal cells so that they could be subjected to different oncogenic patterns-mutations-that would convert the normal cells into cancer cells.

 

"In addition, we developed the first method to effectively generate pulmonary neuroendocrine cell (PNEC), the cell origin for small cell lung cancer (SCLC), by differentiation of hPSCs. The PNECs are physiologically functional and show great similarity to the native ones in human lungs." said Chen. "We were really excited about the results, and we wondered if we could actually model small cell lung cancer using these normal human-origin cells."

 

Such a model would be immensely important. "SCLC is one of the most lethal human malignancies, with metastasis as the major cause of morbidity and mortality in patients. Treatment and diagnosis of SCLC have not been improved over the past 4 decades, partially because fundamental cellular or molecular mechanisms of SCLC have not been well established," said Chen.

 

"Among all solid tumors, SCLC has remarkable metastatic propensity; however, the biological principles of SCLC metastasis remain poorly understood. Progress has been limited due to several obstacles. Because a majority of SCLC patients have already developed metastases at diagnosis, surgical resection is not typically an option. This feature has limited the availability of metastatic tumor samples, especially those with paired primary tumor tissues, for molecular studies and for the generation of SCLC cell lines. Genetically engineered animal models have made contributions to SCLC research; however, in many instances certain hypotheses cannot be tested due to species differences.

 

"On the other hand, modeling SCLC in human cells is a difficult task as pulmonary neuroendocrine cells, the cell of origin of SCLC, are rare airway epithelial cells, and few methods have been established to grow and spread the primary cells," Chen continued. "Therefore, faithful pre-clinical SCLC models are urgently needed and these features of the disease call for new approaches of the sort we have proposed."

 

In a published work, Chen and team described the first method to effectively generate PNECs by directed differentiation of hPSCs, including human embryonic stem cells and inducible pluripotent stem cells (J Exp Med 2019; https://doi.org/10.1084/jem.20181155).

 

"The hPSC-derived PNECs were physiologically functional, presented typical neuroendocrine characteristics, and co-expressed almost all human PNEC markers. By further manipulating RB1 and TP53, genes uniformly inactivated in SCLC, the PNEC populations largely expanded in number in culture and transformed to tumors resembling early-stage SCLC in immunodeficient mice," Chen hPSC. "Of particular significance, by overexpression of wild-type MYC or mutated MYCT58A, with inactivation of RB1 and P53, the PNECs developed the advanced-stage SCLC tumors in mice, displaying increased angiogenesis, invasion into endothelium, and metastasis to distal organs such as lymph node or liver. Further characterization at cellular and molecular levels revealed a great similarity between the hPSC-derived model and human SCLC samples. The studies have demonstrated that a feasible and trackable SCLC model recapitulates the main features of the disease at various stages, and it enables in-depth mechanistic studies of SCLC metastasis in a genetically defined human background."

 

Asked how this emerging research may impact the future of medicine, Chen answered, "I expect the new research platform to answer some fundamental questions about the biology of PNECs, and generate new ideas about prevention, diagnosis, and treatment of SCLC, especially in an era in which stem cell biology, disease modeling, and genomics are approaching a new level of sophistication."

 

Valerie Neff Newitt is a contributing writer.