References of "Ternes, Dominik 50018041"
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See detailFrom meta-genomics to causality: Understanding the role of colon cancer-associated bacteria in colorectal cancer
Ternes, Dominik UL; Wilmes, Paul UL; Letellier, Elisabeth UL et al

Poster (2017, February 05)

The human gastrointestinal tract is home for trillions of bacteria that influence homeostasis and health in a complex biological system: the gut microbiome. Accumulating evidence suggests that a state of ... [more ▼]

The human gastrointestinal tract is home for trillions of bacteria that influence homeostasis and health in a complex biological system: the gut microbiome. Accumulating evidence suggests that a state of pathological imbalance in the microbiome (dysbiosis) is present in patients suffering from colorectal cancer (CRC). To date, microbiome studies identified specific bacteria being associated with dysbiosis in CRC. Some of these bacteria (e.g. Fusobacteria) directly or indirectly interact with cancer and immune cells of their host. However, current studies only focused on certain microbes in detail, hence, their role in the etiology of the disease remains elusive. Accordingly, my project investigates the role of CRC-associated bacteria in tumor initiation and progression while addressing the question: which and what kind of microbes interact with, favor, or can cause CRC? In a first step, we identified CRC-associated bacteria, enriched at the tumor site of Luxembourgish CRC patients. By using Fusobacterium nucleatum as our study model, we predicted and optimized bacterial growth (media) in silico by using a genome-scale metabolic reconstruction model for a constraint-based modelling approach. Next, we assessed bacterial growth and metabolism in the optimized growth medium by using flow cytometry and mass spectrometry. Finally, we co-cultured the bacteria together with primary patient-derived cultures in the recently developed, microfluidics-based, human-microbial cross-talk model (HuMiX) [1]. As part of our ongoing validations, we infected patient-derived, healthy and cancerous 3D colonic organoids with our bacterial candidate. This workflow enables us to analyze pro-tumorigenic capacities of CRC-associated bacteria on healthy and cancerous colonocytes. It will serve as a promising tool for future analysis of host-microbial interaction mechanisms of various CRC-associated bacteria on a transcriptomic, proteomic, and metabolomic level. [1] Shah P, Fritz JV, Glaab E, Desai MS, Greenhalgh K et al. (2016) A microfluidics-based in vitro model of the gastrointestinal human-microbe interface. Nature communications 7: 11535. [less ▲]

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See detailHypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production
Ullmann, Pit UL; qureshi-baig, komal; Rodriguez, Fabien UL et al

in Oncotarget (2016)

Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested to regulate a subpopulation of cancer cells with tumorigenic properties, the so-called tumor ... [more ▼]

Low oxygen concentrations (hypoxia) are known to affect the cellular metabolism and have been suggested to regulate a subpopulation of cancer cells with tumorigenic properties, the so-called tumor-initiating cells (TICs). To better understand the mechanism of hypoxia-induced TIC activation, we set out to study the role of hypoxia-responsive miRNAs in recently established colon cancer patientderived TICs. We were able to show that low oxygen concentrations consistently lead to the upregulation of miR-210 in different primary TIC-enriched cultures. Both stable overexpression of miR-210 and knockdown of its target gene ISCU resulted in enhanced TIC self-renewal. We could validate the tumorigenic properties of miR- 210 in in vivo experiments by showing that ectopic expression of miR-210 results in increased tumor incidence. Furthermore, enhanced miR-210 expression correlated with reduced TCA cycle activity and increased lactate levels. Importantly, by blocking lactate production via inhibition of LDHA, we could reverse the promoting effect of miR-210 on self-renewal capacity, thereby emphasizing the regulatory impact of the glycolytic phenotype on colon TIC properties. Finally, by assessing expression levels in patient tissue, we could demonstrate the clinical relevance of the miR-210/ISCU signaling axis for colorectal carcinoma. Taken together, our study highlights the importance of hypoxia-induced miR-210 in the regulation of colon cancer initiation. [less ▲]

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