Einfluss des Mikrobioms auf Tumorprogression und Tumor-Mikromilieu beim pankreatisch duktalen Adenokarzinom

Bauer, Ann-Kathrin

Thesis

Open Access

Einfluss des Mikrobioms auf Tumorprogression und Tumor-Mikromilieu beim pankreatisch duktalen Adenokarzinom

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dakb.pdf (2.23 MB)

Date

2025-09-29

Authors

Bauer, Ann-Kathrin

Supervisors

Person

Buchholz, Malte

Abstract

As already known, the development of colorectal cancer can strongly be influenced by chronic intestinal inflammation. In contrast to that correlation, the influence of gut inflammation or microbial dysbiosis on the carcinogenesis of the pancreas has to be further examined. Consequently, the chronic inflammation or dysbiosis of the human intestine should be the focus of this thesis, because it could depict a central risk factor of pancreatic carcinogenesis, because of the anatomical vicinity. This goal should be reached by using lysed citrobacter rodentium as a model organism for chronic intestinal inflammation, as well as E.coli as a representative of an intact gut microbiome. Apart from that, human or murine pancreatic cancer cells and THP-1 cells as a macrophage model were used. In this way, the influence of both of the bacterial lysates on the two cell types alone and in combination could be examined in cell culture. The thesis in hand could show that C.rod. was able to influence the viability of different pancreatic cancer cell lines in a positive way and even more than conventional E.coli. Subsequently, it should be examined how far these bacterial lysates could have an impact on THP-1 cells. It was shown that THP-1 cells reacted with a polarization into their M1 status after six hours of stimulation with C.rod. or E.coli. After 6 to 12 hours, there was a change of the polarization into the rather pro-tumorigenic M2 status, which the macrophages could maintain until the end of the 48h observation period. Unfortunately, this effect could not be shown as clearly in the experiment with human macrophages; the results were very inhomogeneous. Next, the impact of S2007 cells on the polarization status of THP-1 should been analyzed. THP-1 cells prepolarized in M2 direction could maintain their status in co-culture with S2007 better than in co-culture with HEK293 cells. After that, bacterial lysate was added to this co-culture, and subsequently, the M2 status of the macrophages was even more increasing; even macrophages that were unpolarized or polarized in M1-direction showed a clear M2 marker expression. Lastly, the effect of gemcitabine on S2007 cells in presence of M1 or M2 macrophages and C.rod. or E.coli lysate should be examined. It seemed that the chemotherapeutic agent did not influence the cells in the expected way, because it had nearly no influence on the cell viability of S2007, despite successful IC50-validation. In conclusion, the importance of the research field of intestinal dysbiosis and its role as a potential risk factor of PDAC development and progression was highlighted one more time. In the future, further analysis of the influence of Citrobacter rodentium lysate on more human and on murine macrophages should be envisaged, as well as an observation of THP-1 cells after stimulation with C.rod. for more than 48 hours. A more detailed analysis of the molecular mechanism underlying the influence of C.rod. on macrophages and tumor cells could be a possible research approach building on these results.