Susan J. Hagen, PhD
Associate Professor of Surgery, Harvard Medical School
Associate Vice Chair for Research, Department of Surgery
Lay-Hong Ang, PhD
Tyler Caron, DVM
Aniket Gad, MS
Yue Li, PhD
Kathleen Scott, DVM
The focus of my laboratory is to understand how barrier dysfunction facilitates gastric cancer development during Helicobacter pylori infection. We approach our work by studying the details of gastric barrier function in general, and its disruption during infection and cancer development using genetic, advanced microscopy, and genomic approaches. Our aims have two important goals: one is to understand basic science principles and the other is translational.
Although the stomach expresses a specific subset of claudin molecules, which are proteins that confer barrier properties to epithelial cells at the tight junction, it highly expresses one particular claudin, claudin-18 (CLDN18). CLDN18 is a cation-specific tight junction protein that is transcriptionally down-regulated in H. pylori infection in mice as well as in human patients with gastric cancer. Because CLDN18 protein and its gene, CLDN18, are attenuated in disease, we made CLDN18 knockout mice to study its role in mucosal barrier function in general and in gastric cancer pathogenesis in particular. Our recent work demonstrates that CLDN18: 1) is not tight junction associated but is rather a basolateral membrane protein (Figure 1). This work was done using super-resolution microscopy techniques by Dr. Ang; 2) is an important signaling molecule that regulates gastric homeostasis; and 3) is a potent tumor suppressor in the stomach. We recently demonstrated that knockout of CLDN18 promotes rapid gastric cancer development. Due to these results, we created two gastric cell-specific conditional knockout mouse lines to genetically dissect the role of CLDN18 in gastric tumorigenesis. We complement the animal studies with in vitro work using primary cultured gastric epithelial cells that contain nearly pure parietal or chief cells, or gastric organoids. We have work in progress to evaluate the role of cytokines in down-regulation of CLDN18 using the reductionist models, with the hypothesis that interleukin-1beta down-regulates CLDN18, leading to gastric cancer development (Figure 2). With collaborators, we also use human pathology samples from gastritis through gastric cancer to evaluate gene-expression patterns for novel biomarkers related to CLDN18 that may inform patient management, drive biomarker development for early screening, and/or uncover therapeutic opportunities for novel drug development targeting gastric cancer.
A second project in the lab involves a close collaboration with Dr. David Cohen, Chief of Gastroenterology and Hepatology at Weil Cornell in New York, to study the role of thioesterase superfamily member 1 (Them1) in hepatic steatosis/NAFDL. We became involved with this project due to our expertise in microscopy, specifically in correlative light (LM) and electron (EM) microscopy. Using adipocytes in culture, we have shown that Them1 associates with glycogen. As metabolism is stimulated, PKC activation via a distinct pathway changes the localization of Them1/glycogen. We are currently working to understand the physiological consequences of the Them1/glycogen interaction and rearrangement after stimulation. For this project, we have been using the new High Pressure Freezer, transfecting cells and expressing EGFP for confocal (LM) and APEXII for EM, and have been using the biotin-labeling technique with APEXII to determine in vivo binding partners for Them1.
Yue Li and I served as mentors for Avi Goyal, a high school student from Chicago, who was in the Research Science Institute’s (RSI) summer research program at MIT. The program ran from June 27-August 3, 2017. Avi worked in the laboratory on the Them1 project.
I served as a mentor for Salih Karahan, a 3rd year medical student from Turkey. Mr. Karahan was in the laboratory June-August 2017 and worked on the gastric cancer project.
I sat on the GMPB study section for 3 grant review sessions in 2016.
Yue Li was awarded a prestigious travel award by the Biophysical Society to attend Experimental Biology 2017. This award included a weekend professional development workshop prior to the meeting.
Yue Li was accepted to attend the Mount Desert Island Biological Labs course for GI Fellows, “Origins and Frontiers of Hepatobiliary and Gastrointestinal Physiology,” in September 2017. Attendance was awarded competitively to a small number of applicants.
Invited Presentations (selected)
“Tight Junctions and Gastric Cancer: Three Critical Concepts.” BK21 PLUS Project for Bioactive Nutrition 2016 Visiting Professor, Department of Food & Nutrition, College of Human Ecology, Yonsei University, Korea, 2016
“Tight Junctions and Gastric Cancer: Three Critical Concepts”. Department of Pharmacology, College of Medicine, Yonsei University, Korea, 2016
Teaching, Training, and Education
In addition to teaching students, technicians, and post-doctoral fellows in the research laboratory, I taught investigators to use the electron microscope and to do electron microscopy (EM) tomography in the EM facility at BIDMC.
IModule Leader in 2016 and 2017 for the Comparative Physiology Course at Mount Desert Island Biological Laboratory. Approximately 12 medical/surgical residents rotated through the module, “Gastric Acid Secretion,” during the one-week course.
GI Fellows Courses
Module Leader in 2017 for a Physiology Course at Mount Desert Island Biological Laboratory. Approximately 12 GI fellows or PhD research fellows rotated through the module, “Gastric Acid Secretion,” during the one-week course.
Selected Research Support
Gastric Cancer Research Fund; 2015-ongoing; PI: Susan J. Hagen, PhD
Them1-mediated metabolic regulation and pathogenic role in NAFLD; NIH, 2015-2020; Multi-PI R01: David E. Cohen, MD, PhD, Weill Cornell Medical College; Susan J. Hagen, PhD; Eric A. Ortlund, PhD, Emory University
Biology of alimentary epithelia in health and disease; NIH, 2015-2020; Microscopy and Histopathology Core B PI: Susan J. Hagen, PhD (PI: Wayne Lencer, MD, Boston Children’s Hospital)
Biomedical research training for veterinary scientists; NIH, 2013-2018; Academic Mentor: Susan J. Hagen, PhD (PI: James G. Fox, DVM, MIT)
Live-cell LSM 880 confocal microscope; BIDMC Capital Investment Award, 2017
Palmer CJ, Bruckner RJ, Paulo JA, Kazak L, Long JZ, Mina AI, Deng Z, LeClair KB, Hall JA, Hong S, Zushin P-JH, Smith KL, Gygi SP, Hagen SJ, Cohen DE, Banks AS. Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue. Mol Metab 2017;6(10):1212-25.
Hagen SJ. Non-canonical functions of claudin proteins: beyond the regulation of cell-cell adhesions. Tissue Barriers 2017;5(2):e1327839.
Desai A, Alves-Bezerra M, Li Y, Ozdemir C, Bare CJ, Li Y, Hagen SJ, Cohen DE. Regulation of fatty acid trafficking in liver by thioesterase superfamily member 1 and contribution to hepatic steatosis in mice. J Lipid Res 2017; in press.