PROJECT 1 ABSTRACT Esophageal cancer comprises two major subtypes, namely esophageal squamous cell carcinoma (ESCC), and esophageal adenocarcinoma (EAC). Esophageal cancer poses grave and pressing clinical problems in the United States and worldwide as reflected by the increasing incidence of EAC in the US, and of the worse prognoses of any cancers as evident in ESCC worldwide. We are focusing on the p120catenin (p120ctn) or CTNND1 and TP53 tumor suppressor genes. Tumor cell progression is illustrated by invasion into the extracellular matrix (ECM) or stoma. This then involves interrelated networks between tumor cells and diverse cell types in the tumor microenvironment. This cross-talk and cross-fertilization trigger a necessary cascade of events prior to dissemination of tumor cells into blood and lymphatic vessels, as well as local and distant metastasis. These include, but are not restricted to, immune cells/inflammatory cells, fibroblasts, endothelial cells, pericytes, neurons, and adipocytes. Our unified view is that p120ctn loss or mislocalization, either of which abrogates its tumor suppressor activities involved in the maintenance of the adherens junctions (complex with E-cadherin) fosters tumor initiation as revealed by our published work on the conditional loss of p120ctn in the mouse esophagus, resulting in invasive ESCC (with local metastasis to lymph nodes) accompanied by desmoplasia and the specific recruitment of myeloid derived suppressor cells (MDSCs) or immature myeloid cells. Tumor progression requires the acquisition of TP53 mutations, which conspire to drive further tumor invasion. The tumor cells interact with cancer-associated fibroblasts (CAFs) and these MDSCs in the tumor microenvironment, involving in part the IL-6 master cytokine that is pro-inflammatory and pro- tumorigenic. Thus, our overarching hypothesis is that p120ctn and TP53 proteins cooperate in tumor progression, TP53 mutation triggers an invasive gene signature that drives tumor cells to invade into the ECM and remodel the ECM, and that tumor invasion in the microenvironment involves the interactions between tumor cells, CAFs and MDSCs. This hypothesis will be pursued by the following interrelated Specific Aims.
Aim 1 : To evaluate CD38 induction in MDSC populations and its role in immunosuppression via iNOS activation.
Aim 2 : To elucidate the functional roles of IL-6 as a mediator of cross talk between tumor cells and CAFs in the ESCC microenvironment.
Aim 3 : To elucidate the functional interplay between p120ctn and TP53 in the esophageal tumor microenvironment. Our successful achievement of these Specific Aims is facilitated greatly by the synergy between the exceptional Projects and the exceptional support provided by the Core Facilities, apart from the broad and deep institutional support.

Public Health Relevance

PROJECT 1 NARRATIVE Our work takes a unified view of elucidating mechanisms underlying esophageal tumor initiation and progression, as a platform for the evaluation of therapeutics in new preclinical models. Ultimately, we seek to translate these discoveries and findings into improved patient and clinical outcomes in esophageal cancer, which have been elusive to date.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA098101-11
Application #
8741115
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Project Start
2002-12-01
Project End
2019-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$358,285
Indirect Cost
$101,296
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhou, Jin; Wu, Zhong; Wong, Gabrielle et al. (2017) CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma. Nat Commun 8:13897
Whelan, K A; Chandramouleeswaran, P M; Tanaka, K et al. (2017) Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance. Oncogene 36:4843-4858
Whelan, Kelly A; Merves, Jamie F; Giroux, Veronique et al. (2017) Autophagy mediates epithelial cytoprotection in eosinophilic oesophagitis. Gut 66:1197-1207
Harmeyer, Kayla M; Facompre, Nicole D; Herlyn, Meenhard et al. (2017) JARID1 Histone Demethylases: Emerging Targets in Cancer. Trends Cancer 3:713-725
Facompre, Nicole D; Sahu, Varun; Montone, Kathleen T et al. (2017) Barriers to generating PDX models of HPV-related head and neck cancer. Laryngoscope 127:2777-2783
Yoshioka, Masahiro; Ohashi, Shinya; Ida, Tomomi et al. (2017) Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells. J Exp Clin Cancer Res 36:101
Natsuizaka, Mitsuteru; Whelan, Kelly A; Kagawa, Shingo et al. (2017) Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat Commun 8:1758
Giroux, VĂ©ronique; Lento, Ashley A; Islam, Mirazul et al. (2017) Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. J Clin Invest 127:2378-2391
Fichter, Christiane Daniela; Przypadlo, Camilla Maria; Buck, Achim et al. (2017) 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 243:481-495
Facompre, Nicole D; Harmeyer, Kayla M; Sole, Xavier et al. (2016) JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers. Cancer Res 76:5538-49

Showing the most recent 10 out of 149 publications