Our long-term objective is to develop new therapies for esophageal squamous cell carcinoma (ESCC) that are based on the unique biological characteristics of this malignancy. Our working hypothesis is that tumor cells establish a dominant relationship with stromal cells to control the formation of a primitive 'organ', in which all cellular constituents contribute to tumor cell growth, survival and invasion. We then hypothesize that tumor cell resistance to conventional therapies is due to intrinsic and microenvironmental factors. In preliminary studies we have developed three-dimensional culture models of the normal esophagus and of ESCC tumors that mimic conditions in vivo. These models allow us to dissect the roles for each cell type in a tissue-like context to determine how tumors progress and resist therapeutic drugs. This hypothesis will be pursued by the following interrelated Specific Aims: 1) To determine and define the functional synergy between stromal fibroblasts, endothelial cells, and ESCC cells with a focus upon the interplay between stromal fibroblasts and endothelial cells to nurture the microenvironment for esophageal tumor cells. To that end, tumors represent a finely tuned 'organ'in which the malignant cells dominate to drive activationof fibroblasts for matrix and growth factor production. Activated fibroblasts in turn attract endothelial cell and induce their differentiation for vessel formation and provide positive feedback for the tumor cells. We will analyze the secretion of soluble mediators (eg TGFbeta) and the dynamics of cell-cell interactions that together increase the invasive nature of tumors;2) We will develop strategies to overcome the strong resistance of ESCC cells to current therapy. We believe that the unusual resistance to drugs is due to both microenvironmental and intrinsic cues. We will target the fibroblast-endothelial axis. In the second strategy, we have identified a proteasome inhibitor, Bortezomib, as very active. We will determine how we can enhance it's efficacy in SCC and plan to use it in combination with radiation and pro-apototic agents. Project 2 is closely integrated with Project 1 (Aims 2 and 3) and Project 3 (Aims 1 and 3), and makes extensive use of the outstanding, cohesive core facilities.

Public Health Relevance

This Project focuses upon how activated fibroblasts impact upon endothelial cells to nurture neo- angiogenesis in the esophageal tumor microenvironment, which is very critial for tumor cell maintenance and growth. New stratagies are being developed to disrupt this axis and understand the role of novel biological modifiers in the tumor microenvironment and in vivo. Success has been achieved already in taking one approach to a Phase Ib clinical protocol _^_

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA098101-08
Application #
8322183
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
8
Fiscal Year
2011
Total Cost
$65,081
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Giroux, Véronique; Stephan, Julien; Chatterji, Priya et al. (2018) Mouse Intestinal Krt15+ Crypt Cells Are Radio-Resistant and Tumor Initiating. Stem Cell Reports 10:1947-1958

Showing the most recent 10 out of 173 publications