This is an application for the Tumor Microenvironment Network from a highly collaborative group of investigators from Columbia University who have worthed together for over 5 years on the tumor microenvironment. The focus of the program is the role of myofibroblasts (MF)/cancer-associated fibroblasts (CAF) in digestive cancers, and includes studies of gastric, hepatocellular and pancreatic cancer. The three cancers are among the most common and lethal of solid tumors, and evidence suggests that each is strongly promoted at early stages by alpha-SMA+ fibroblastic cells. In addition, recent work suggests that Helicobacter-dependent gastric cancer is promoted by CAFs that are derived from bone marrow derived mesenchymal stem cell (MSCs) and that contribute to the MSC and tumor niche; that hepatocellular cancer is promoted by myofibroblasts that are activated by the microbiome and TLR4 signaling; and that CAFs in digestive cancers show early global DNA hypomethylation with focal gains or promoter methylation, that results in a unique susceptibility to further loss of DNA methylation. Based on these and other observations, three highly interactive projects are proposed. Project 1 (Wang) will further explore the MSC origin of gastric cancer MF/CAFs, their interaction with microbiome signals, their contribution to cancer growth, and the mechanism of hypomethylation; Project 2 (Schwabe) will explore the role of damage-associated molecular patterns (DAMPs), TLR4, and the microbiome to the tumor-promoting myofibroblast niche; Project 3 (Tycko) will examine the relationship of pancreatic and hepatocellular CAF hypomethylation to changes in gene expression and in vivo behavior, and examine the effects of decitabine or conditional Dnmtl KO in CAFs on prevention of tumor progression. The three projects will jointly address the three major themes which are the origins of CAFs, their activation by the gut microbiome, and the role of DNA hypomethylation. The three projects are supported by an Administrative/Bioinformatics Core and by a Germ-Free Mouse Core at MIT. The three projects are highly translational with heavy use of human tissues and physiological mouse models of digestive cancers, and are linked to a Phase 1 clinical trial in human patients with pancreatic cancer.

Public Health Relevance

This study will address the origins and importance of stromal fibroblasts in gastric cancer, liver cancer and pancreatic cancer with a particular focus on the role of commensal bacteria, DNA methylation and the origins of stromal fibroblasts. Understanding how cancer fibroblasts arise and the ways in which they contribute to the growth of tumors will clarify the utility and proper design of therapies targeted to the stroma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163111-05
Application #
8902031
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Woodhouse, Elizabeth
Project Start
2011-09-22
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Caviglia, Jorge Matias; Yan, Jun; Jang, Myoung-Kuk et al. (2018) MicroRNA-21 and Dicer are dispensable for hepatic stellate cell activation and the development of liver fibrosis. Hepatology 67:2414-2429
Boggs, Kristin; Venkatesan, Nandakumar; Mederacke, Ingmar et al. (2016) Contribution of Underlying Connective Tissue Cells to Taste Buds in Mouse Tongue and Soft Palate. PLoS One 11:e0146475
Mu, Xueru; Pradere, Jean-Philippe; Affò, Silvia et al. (2016) Epithelial Transforming Growth Factor-? Signaling Does Not Contribute to Liver Fibrosis but Protects Mice From Cholangiocarcinoma. Gastroenterology 150:720-33
Pradère, Jean-Philippe; Hernandez, Céline; Koppe, Christiane et al. (2016) Negative regulation of NF-?B p65 activity by serine 536 phosphorylation. Sci Signal 9:ra85
Mu, Xueru; Español-Suñer, Regina; Mederacke, Ingmar et al. (2015) Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J Clin Invest 125:3891-903
Manuel, Edwin R; Chen, Jeremy; D'Apuzzo, Massimo et al. (2015) Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors. Cancer Immunol Res 3:1096-107
Duann, Pu; Li, Haichang; Lin, Peihui et al. (2015) MG53-mediated cell membrane repair protects against acute kidney injury. Sci Transl Med 7:279ra36
Caviglia, Jorge Matias; Schwabe, Robert F (2015) Mouse models of liver cancer. Methods Mol Biol 1267:165-83
Luedde, Tom; Kaplowitz, Neil; Schwabe, Robert F (2014) Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147:765-783.e4
Huebener, Peter; Gwak, Geum-Youn; Pradere, Jean-Philippe et al. (2014) High-mobility group box 1 is dispensable for autophagy, mitochondrial quality control, and organ function in vivo. Cell Metab 19:539-47

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