Member Spotlight: Hiroshi Nakagawa, MD, PhD

Dr. Hiroshi Nakagawa’s broad background in gastrointestinal epithelial biology and tumor biology has led to key discoveries and developments in the space of esophageal cancers. In particular, his research has uncovered new insights into esophageal squamous cell carcinoma (ESCC), the deadliest of all human squamous cell carcinomas and common worldwide. He developed the first transgenic mouse model of ESCC, enabling researchers to more precisely explore this disease and potential therapy options.  Over the years, Dr. Nakagawa and his lab has provided expertise in all aspects of isolation, characterization, and pharmacological and genetic modifications of primary mouse and human esophageal cells, establishing cell lines, and development of 3D organoids that mimic esophageal cancer.

Dr. Nakagawa is a member of the Herbert Irving Comprehensive Cancer Center (HICCC) and an associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons. He joined the HICCC in July 2019 after spending 21 years at the University of Pennsylvania in the Division of Gastroenterology and as associate director of Penn’s Cell Culture and iPS Core.

As a member of the Precision Oncology and Systems Biology research program, he continues his work at Columbia in investigating the fundamental mechanisms of esophageal cancers as well as other gastrointestinal (GI) cancers, including the oral cavity and the lung. 

Tell us about your research.

A: We study the esophagus using mouse models and cell culture models to understand the molecular basis of how disease occurs, how cancer develops and progresses in concert with environmental risk factors like tobacco and alcohol, and in some cases, pathogenic microorganisms such as human papillomavirus (HPV).

Microorganisms and their role in GI cancers have been a lingering question in the field. I did my postdoctoral research at Massachusetts General Hospital, under [HICCC Director] Anil Rustgi. When I joined his lab, HPV was a fascinating area because of its potential contribution in initiating esophageal cancer. HPV causes cervical cancer as well as head and neck cancers. Prior research uncovered that HPV could lead to esophageal cancers. My earlier research focused on cell machineries that regulate cell division cycles that are often targeted by HPV and other environmental carcinogens for malignant transformation, a process where normal esophageal cells gain cancer cell properties, including indefinite growth. My research has further evolved to understand how important cell signaling pathways are altered to influence cell functions and characters during cancer development and progression.

What is your lab currently working on?

A: One of our most exciting projects right now looks  to extend our ability to grow patient biopsies derived from a tiny piece of the esophagus into 3D cell culture products—organoids. Patient-derived organoids have a profound potential in personalized medicine. Once we have a tissue specimen from a patient, we can rapidly grow, from a single cell suspension, a patient’s original tumor into a 3D structure in test tubes. This structure, or organoid, mimics the original tumor, whether benign or malignant, and we can then offer analyses, molecular-level sequencing, or conduct treatment experiments by using these organoids as our disease models. One key aspect of this is our ability to test, identify, and potentially predict the drugs that will work best for each cancer patient. These cell culture techniques that we are utilizing in our research require only less than two weeks to complete, rapidly increasing the pace of our studies. We are moving toward clinical translational application of our studies with colleagues at Columbia from both the Division of Digestive and Liver Diseases and at the College of Dental Medicine. 

How did you get interested in this field, and why GI cancer?

A: After finishing medical school at Okayama University in Japan, where I’m from, I was more focused on specializing in liver diseases. Liver diseases and liver cancer at the time—this was about 30 years ago—was a really big problem in the country. Many people in Japan suffered from liver disease. My mother died of liver cancer that arose from chronic viral hepatitis. I did my research in examining the role of hepatitis viruses in liver disease progression. I also considered focusing on gastrointestinal disease at the time because my father was a physician scientist at an academic setting who studied autoimmunity in liver diseases. In a sense, I wanted to follow in his footsteps. In the mid-60’s, my father did a research fellowship in Jacksonville, FL. My family lived there for two years and I went to a nursery school there. Orange juice, peanut butter and jelly sandwiches, SPAM, and KFC became my comfort foods. When I was young, my dream was to come back to the U.S.

I began my academic research career at Okayama University but I wanted to work in a more advanced setting and return to the United States. In 1993, I joined Anil’s lab at Mass General to broadly study esophageal, pancreas, and colon cancers. At Mass General, I studied the gene, cyclin D1, to find that it is over-expressed in esophageal cancer; that work led to establishing the first genetically engineered mouse model for esophageal cancer. I actually collaborated under Anil with Dr. Tim Wang on this project. I had a tremendous opportunity to receive wonderful mentorship under both Anil and Tim, and I continued to focus on GI cancers after joining Anil at Penn. 

What is the overall goal(s) of your work?

A: My ultimate goal is to translate my research into patient care, and continue to focus on esophageal cancer prevention. Over the years I have been working on modeling this disease. Now we can mimic metastatic esophageal cancer in mice models. We are focused on uncovering the various stages of both oral and esophageal cancers. We want to know what initiates early stage of cancer development and how best to detect those invisible lesions. Pathology may not always be able to see some of these changes at the very early stage in cancer development. With the technology advancements now we are hoping to prove that our organoids from patient biopsies can reveal these changes. From gaining this knowledge we can get closer to a cure or a way to prevent cancer progression. 

What motivates your research?

A: I am focused on translating what we learn at the bench to the patient. When I was younger and saw patients as a resident GI fellow, I saw with my own eyes how the patient suffers from this illness. What I would do then as a resident is sit by their side, help them through their pain, and listen patiently to them and to their family members. I think about that time often; I want to help those patients and their families, and alleviate any of their suffering.

After a long career at University of Pennsylvania, what drew you to Columbia and the HICCC?

A: This is one of the best moves I’ve made. After 21 years at Penn, I really wanted to change my environment. It was difficult and sad to learn that Anil, my mentor for 25 years, decided to leave Penn for Columbia. Later I was thrilled to have the opportunity to join him – and many of my existing collaborators in GI research – at Columbia and the HICCC.

As a scientist, I am amazed at how our body structures and functions as a system, tightly woven together from the level of DNA through visible anatomical body parts. I’m very interested in integrating our cell culture models with a systems biology approach. Systems biology is a major strength here and one of the main reasons why I came to Columbia. I’ve already met so many colleagues who are willing to help utilize their expertise towards some of our goals to understand the biology of GI cancers and eventually help in translating our findings into patient care.