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
Wong, Gabrielle S; Zhou, Jin; Liu, Jie Bin et al. (2018) Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med 24:968-977
Karakasheva, Tatiana A; Dominguez, George A; Hashimoto, Ayumi et al. (2018) CD38+ M-MDSC expansion characterizes a subset of advanced colorectal cancer patients. JCI Insight 3:
Liu, Yang; Sethi, Nilay S; Hinoue, Toshinori et al. (2018) Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas. Cancer Cell 33:721-735.e8
Facompre, Nicole D; Harmeyer, Kayla M; Sahu, Varun et al. (2018) Targeting JARID1B's demethylase activity blocks a subset of its functions in oral cancer. Oncotarget 9:8985-8998
Deng, Jiehui; Wang, Eric S; Jenkins, Russell W et al. (2018) CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov 8:216-233
Karakasheva, Tatiana A; Lin, Eric W; Tang, Qiaosi et al. (2018) IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment. Cancer Res 78:4957-4970
Kasagi, Yuta; Chandramouleeswaran, Prasanna M; Whelan, Kelly A et al. (2018) The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes. Cell Mol Gastroenterol Hepatol 5:333-352
Pectasides, Eirini; Stachler, Matthew D; Derks, Sarah et al. (2018) Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. Cancer Discov 8:37-48
Campbell, Joshua D; Yau, Christina; Bowlby, Reanne et al. (2018) Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. Cell Rep 23:194-212.e6
Whelan, Kelly A; Muir, Amanda B; Nakagawa, Hiroshi (2018) Esophageal 3D Culture Systems as Modeling Tools in Esophageal Epithelial Pathobiology and Personalized Medicine. Cell Mol Gastroenterol Hepatol 5:461-478

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