Hiroshi Nakagawa

faculty photo
Research Associate Professor of Medicine
Department: Medicine

Contact information
Division of Gastroenterology
421 Curie Boulevard
956 Biomedical Research Building
Philadelphia, PA 19104
Office: 215-573-1867
Fax: 215-573-2024
Graduate Group Affiliations
Education:
MD
Okayama University, Okayama, Japan, 1989.
Ph.D.
Okayama University (Medical Science) Okayama, Japan, 1993.
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Description of Research Expertise

A major goal of my laboratory is to understand the molecular mechanisms by which the tumor microenvironment fosters esophageal tumor initiation and progression. Currently, I investigate how factors such as hypoxia and transforming growth factor (TGF)-β induce epithelial-to-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) cells. In addition, I have been exploring the roles of the Notch signaling in esophageal epithelial homeostasis, malignant transformation and cancer stem cells. Notch signaling and TGF-β regulate cooperatively EMT and foster resistance to conventional chemotherapy. I have a broad background in gastrointestinal epithelial biology, tumor biology, and molecular and cellular biology with specific training and expertise in key research areas.

As a postdoctoral fellow at the Massachusetts General Hospital, I worked on fundamental cell cycle regulation and gene transcription in esophageal squamous epithelial cell model systems, using both in vitro and in vivo approaches. I investigated the transcriptional regulation of viral and cellular promoters that are active in the esophageal epithelium, with the identification of cis-regulatory elements and trans-activating factors, cross-regulating the Epstein-Barr virus ED-L2 promoter and keratin promoters. I used this as a platform for utilizing the EBV ED-L2 promoter to target genes (e.g. cyclin D1) in transgenic mice.

As faculty member at the Gastroenterology Division of the University of Pennsylvania, I expanded my research to include epidermal growth factor receptor (EGFR) oncogene. As PI of several previous university, private (American Gastroenterological Association Research Scholar Award), and NIH-funded grants (K01, K26, R21 and R01), I have developed primary and immortalized human and mouse esophageal epithelial cell culture systems, human tissue engineering in organotypic 3D culture, a form of human tissue engineering, and xenograft transplantation and genetically engineered mouse models coupled with in vivo molecular imaging.

I successfully administered the projects (e.g. staffing, research protections, budget), collaborated with other researchers, and produced several peer-reviewed publications from each project. I have mentored a visiting faculty member, nine postdoctoral research fellows, including young clinician-scientists, and graduate and undergraduate students.

In addition, I serve as Associate Director of Cell Culture Core at the University of Pennsylvania Perelman School of Medicine. We provide a centralized repository of human and mouse-derived normal and engineered as well as cancer cell lines including numerous esophageal and head and neck squamous cell carcinoma cell lines. We also produce retroviruses and lentiviruses for gene transduction experiments, and preparation of organotypic 3D culture substrates (fibroblasts-matrix) and required media.

Description of Itmat Expertise

Esophageal cancers
Tumor microenvironment
Notch signaling

Selected Publications

Wong Gabrielle S, Habibollahi Peiman, Heidari Pedram, Lee Ju-Seog, Klein-Szanto Andres J, Waldron Todd J, Gimotty Phyllis, Nakagawa Hiroshi, Taylor Philip R, Wang Timothy C, Mahmood Umar, Rustgi Anil K: Optical imaging of periostin enables early endoscopic detection and characterization of esophageal cancer in mice. Gastroenterology 144(2): 294-7, Feb 2013.

Wong G S, Lee J-S, Park Y-Y, Klein-Szanto A J, Waldron T J, Cukierman E, Herlyn M, Gimotty P, Nakagawa H, Rustgi A K: Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment. Oncogenesis 2: e59, 2013.

Natsuizaka Mitsuteru, Naganuma Seiji, Kagawa Shingo, Ohashi Shinya, Ahmadi Azal, Subramanian Harry, Chang Sanders, Nakagawa Kei J, Ji Xinjun, Liebhaber Stephen A, Klein-Szanto Andres J, Nakagawa Hiroshi: Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Mar 2012.

Kalabis Jiri, Wong Gabrielle S, Vega Maria E, Natsuizaka Mitsuteru, Robertson Erle S, Herlyn Meenhard, Nakagawa Hiroshi, Rustgi Anil K: Isolation and characterization of mouse and human esophageal epithelial cells in 3D organotypic culture. Nature protocols 7(2): 235-46, Feb 2012.

Gu Y, Lin S, Li J-L, Nakagawa H, Chen Z, Jin B, Tian L, Ucar D A, Shen H, Lu J, Hochwald S N, Kaye F J, Wu L: Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion. Oncogene 31(4): 469-79, Jan 2012.

Predina J D, Judy B, Aliperti L A, Fridlender Z G, Blouin A, Kapoor V, Laguna B, Nakagawa H, Rustgi A K, Aguilar L, Aguilar-Cordova E, Albelda S M, Singhal S: Neoadjuvant in situ gene-mediated cytotoxic immunotherapy improves postoperative outcomes in novel syngeneic esophageal carcinoma models. Cancer gene therapy 18(12): 871-83, Dec 2011.

Ohashi Shinya, Natsuizaka Mitsuteru, Naganuma Seiji, Kagawa Shingo, Kimura Sotai, Itoh Hiroshi, Kalman Ross A, Nakagawa Momo, Darling Douglas S, Basu Devraj, Gimotty Phyllis A, Klein-Szanto Andres J, Diehl J Alan, Herlyn Meenhard, Nakagawa Hiroshi: A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors. Cancer research 71(21): 6836-47, Nov 2011.

Yang Yizeng, Nakagawa Hiroshi, Tetreault Marie-Pier, Billig Janelle, Victor Noel, Goyal Abha, Sepulveda Antonia R, Katz Jonathan P: Loss of transcription factor KLF5 in the context of p53 ablation drives invasive progression of human squamous cell cancer. Cancer research 71(20): 6475-84, Oct 2011.

Heeg Steffen, Hirt Nina, Queisser Angela, Schmieg Hannah, Thaler Michaela, Kunert Heike, Quante Michael, Goessel Gitta, von Werder Alexander, Harder Jan, Beijersbergen Roderick, Blum Hubert E, Nakagawa Hiroshi, Opitz Oliver G: EGFR overexpression induces activation of telomerase via PI3K/AKT-mediated phosphorylation and transcriptional regulation through Hif1-alpha in a cellular model of oral-esophageal carcinogenesis. Cancer science 102(2): 351-60, Feb 2011.

Ohashi Shinya, Natsuizaka Mitsuteru, Nakagawa Hiroshi: MMP7 and activation of IGF-1R: a new insight into anti-EGFR therapeutic resistance in metastatic colorectal cancer. Cancer biology & therapy 11(2): 184-7, Jan 2011.

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Last updated: 08/13/2014
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