PhD Dissertation Defense-Hacer Ezgi Karakaş Schüller
  • FENS
  • PhD Dissertation Defense-Hacer Ezgi Karakaş Schüller

You are here

TUMOR-STROMA COMMUNICATION THROUGH ACTIVATION OF AUTOPHAGY IN FIBROBLAST CELLS, AN IMPORTANT COMPONENT OF STROMA

 

Hacer Ezgi Karakaş Schüller
Molecular Biology, Genetics and Bioengineering, Ph.D. Dissertation, 2017

 

Thesis Jury

Assoc. Prof. Devrim Gözüaçık (Thesis Advisor),

Prof. Ali Koşar, Assoc. Prof. N.C. Tolga Emre, Prof. Yoon-Kyoung Cho (Ulsan National Institute of Science and Technology), 

Distinguished Prof. François Amblard (Ulsan National Institute of Science and Technology)

 

 

Date & Time: August 1st, 2017 – 10:30 AM

Place: FENS G035

Keywords: Autophagy, Cancer, Tumor Microenvironment, Biochips, Cell-Cell Communication

 

Abstract

 

Autophagy is an evolutionary conserved stress response mechanism. A bulk of cytoplasm including organelles or proteins is engulfed by a double membrane structure and later on degraded by fusion with the lysosome in order to provide building blocks for the need of the cell under stress conditions such as lack of nutrients or hypoxia. This mechanism has an important role in health as well as onset or the progress of different diseases including cancer. The communication between cancer and its surrounding cells, herein called microenvironment or stroma, is crucial for the initiation, progression and metastasis of the cancer cells. Basically, the tumor microenvironment provides a basis (soil) for the growth of cancer cells (seed). One of the major component of the stroma is fibroblast cells. They are known to be activated during tumorigenesis to support the survival and proliferation of cancer cells by reshaping the environment, and by providing growth factors and metabolites. During cancer cell-fibroblast cell communication, cancer cells cause induction of autophagy in fibroblast cells and they benefit from autophagy by using the secreted metabolites from fibroblast cells. However, it is not elucidated yet how cancer cells initiate this communication with surrounding cells to activate their autophagy, especially in fibroblasts. This information is important to prevent the support of fibroblast cells to cancer cells. In this thesis, the main aim is to mimick cancer‑fibroblast communication outside of the body in order to define the key factors which initiate the crosstalk between cancer cells and fibroblasts through the modulation of autophagy. To create a sensitive system, microfluidic chips, or biochips, were used to monitor the crosstalk between single cancer cells with fibroblast cells through autophagy analysis in fibroblast cells. Moreover, a human growth factor and cytokine cDNA library was screened in order to cover potential communication signals broadly. According to the results, novel soluble paracrine factors were found to significantly induce autophagy in fibroblast cells. In order to create organized tissues outside of the body, 3D bioprinting of fibroblast cells was performed. During the preparation and bioprinting process, the importance of autophagy was tested using autophagy-competent (MEF WT) and autophagy deficient ((Atg5-/-) MEF) cells. In summary, our research about microfluidic chip system shows the potential of this platform to analyze individual single cancer cells which can activate autophagy in fibroblasts, our researches about novel factors broaden our perspective in order to study the communication signal between cancer cell with fibroblasts in autophagy, and our research about 3D bioprinting shows the importance of autophagy during cell-cell communication in artificially created organized structures.