Analyzing the impact of the tumor microenvironment on esophageal carcinogenesis

• Applicant: Professor Dr. Michael Quante
• Subject Area: Gastroenterology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323308640

Barretts Esophagus (BE) represents the initial step in the progression to esophageal adenocarcinoma (EAC) which incidence has increased greater than any other cancer. Therefore, there is a critical need to develop preventive strategies and therapies for a growing population of BE patients. However, the development of surveillance strategies and chemoprevention therapies for BE has been severely restricted by the absence of a tractable pre-clinical model. To address this need we have developed a mouse model of BE that resembles human pathology and demonstrates that BE arises from a cardia stem cell, a paradigm change. Accumulating evidence demonstrated that stem cells are strongly influenced by the host microenvironment and it has been shown that the lifetime risk of cancers is correlated with the number of stem cell divisions. Thus, in order to design better preventive and therapeutic strategies for BE and EAC, it will be of tremendous importance to understand the function and contribution of the tumor microenvironment.In this project we aim to utilize the first inflammatory transgenic mouse model of BE/EAC, a 3D organotypic in vitro culture system of BE, and biopsies of human patients at different time points during progression to EAC to analyze the importance and function of cancer associated fibroblasts (CAFs) in the microenvironment during the development of BE and EAC and the impact of these cells on stem cells and cancer initiating cells. We propose that a specific inflammatory microenvironment contains specific CAFs that promote esophageal carcinogenesis by recruiting epithelial tem cells, promoting cell proliferation, apoptosis, migration and consequently inducing mutagenesis and malignant transformation of epithelial (stem) cells. The detection of specific factors or cell types within a tumorigenic niche would define a ground breaking novel modality that allows do define a population at risk to develop EAC, this finding could be extrapolated to other inflammation induced cancers and help to develop new preventive and therapeutic strategies. In our prior work we could demonstrate that CAFs can induce such a phenotype in gastric cancer.

• DFG Programme: Research Grants