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.
Kasagi Y, Chandramouleeswaran PM, Whelan KA, Tanaka K, Giroux V, Sharma M, Wang J, Benitez AJ, DeMarshall M, Tobias JW, Hamilton KE, Falk GW, Spergel JM, Klein-Szanto AJ, Rustgi AK, Muir AB, Nakagawa H: The Esophageal Organoid System Reveals Functional Interplay between Notch and Cytokines in Reactive Epithelial Changes Cell Mol Gastroenterol Hepatol 5(3) : 333-52,2018.
Fichter C, Przypadlo C, Buck A, Bittermann N, Riedel B, Schaefer L, Nakagawa H, Walch A, Reinheckel T, Werner M, Lassmann S: A new model system identifies epidermal growth factor receptor-human epidermal growth factor receptor 2 (HER2) and HER2-human epidermal growth factor receptor 3 heterodimers as potent inducers of oesophageal epithelial cell invasion J Pathol 243 (4): 481-95,2017.
Natsuizaka M, Whelan KA, Kagawa S, Tanaka K, Giroux V, Chandramouleeswaran PM, Long A, Darling DS, Que J, Yang Y, Katz JP, Wileyto EP, Basu D, Kita Y, Natsugoe S, Naganuma S, Klein-Szanto AJ, Diehl JA, Bass AJ, Wong KK, Rustgi AK, Nakagawa H: Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma Nature Communications 8 (1): 1758,2017.
Maehara O, Suda G, Natsuizaka M, Ohnishi S, Komatsu Y, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, Shimazaki T, Kimura M, Asano A, Fujimoto Y, Ohashi S, Kagawa S, Kinugasa H, Naganuma S, Whelan KA, Nakagawa H, Nakagawa K, Takeda H, Sakamoto N: Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma Carcinogenesis 38 (11): 1073-1083,2017.
Whelan KA, Tanaka K, Chandramouleeswaran PM, Kagawa S, Guo A, Guha M, Srinivasan S, Facompre N, Klein-Szanto AJ, Amaravadi RK, Basu D, Avadhani NG, Rustgi AK and Nakagawa H: Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin2-mediated mitochondrial clearance Oncogene 36 (34): 4843-4858,2017.
Whelan KA, Merves JF, Giroux V, Tanaka K, Guo A, Chandramouleeswaran PM, Benitez AJ, Dods K, Que J, Masterson JC, Fernando SD, Godwin BC, Klein-Szanto AJ, Chikwava K, Ruchelli ED, Hamilton KE, Muir AB, Wang ML, Furuta GT, Falk GW, Spergel JM, Nakagawa H: Autophagy mediates epithelial cytoprotection in eosinophilic oesophagitis Gut 66 (7): 1197-1207,2017.
Giroux V, Lento A, Islam MM, Pitarresi J, Kharbanda A, Hamilton K, Whelan K, Long A, Rhoades B, Tang Q, Nakagawa H, Lengner C, Bass A, Wileyto EP, Klein-Szanto A, Wang T, Rustgi A: Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration J Clin Invest 127 (6): 2378-91,2017.
Noguchi C, Grothusen G, Anandarajan V, Martínez-Lage GM, Terlecky D, Corzo K, Tanaka K, Nakagawa H, Noguchi E: Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast Cell Cycle 16 (1): 45-58,2017.
Guha M, Srinivasan S, Guja KE, Mejía E, Garcia-Diaz M, F. Brad Johnson FB, Ruthel G, Kaufman B, Rappaport E, Glineburg R, Fang J, Klein-Szanto AJ, Nakagawa H and Avadhani NG: HnRNPA2 is a novel histone acetyltransferase which mediates mitochondrial stress induced nuclear gene expression Cell Discovery 2 : 16045,2016.
Facompre ND, Harmeyer KM, Sole X, Kabraji S, Belden Z, Sahu V, Whelan KA, Tanaka K, Weinstein GS, Montone KT, Roesch A, Gimotty PA, Herlyn M, Rustgi AK, Nakagawa H, Ramaswamy S, Basu D: JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers Cancer Research 76 (18): 5538-49,2016.
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