Role of microbiota in bladder cancer development - µBC

(Research project)

Project leader: prof. Janoš Terzić, MD

Project duration: 08.03.2021. - 07.03.2025. 

Postdoctoral fellow:
Blanka Roje, PhD

PhD students:
Maria Bošković, mag. mol. biol. 
Dora Knezović, MD

Assistant prof. Jelena Korać Prlić, University of Split, School of Medicine, Split, Croatia 
Assistant prof. Marina Degoricija, University of Split, School of Medicine, Split, Croatia 
Prof. Katarina Vilović, University of Split, School of Medicine and University hospital Split, Split, Croatia 
Prof. Marijan Šitum, University of Split, School of Medicine and University hospital Split, Split, Croatia 
Prof. Ozren Polašek, University of Split, School of Medicine, Split, Croatia (until 31.01.2023.)
Michael Zimmermann, PhD, EMBL Heidelberg, Njemačka

Bladder cancer (BC) is the fourth most common cancer in men after prostate, lung and colon cancer. It is three to four times more common in men than in women. Bladder cancer can be caused by chronic infection with Schistosoma haematobium, while the main therapeutic approach is infection with Bacillus Calmette Guerin (BCG). These facts clearly highlight the importance of microbes (microbiota) in the pathogenesis of bladder cancer. Recent research, including ours, has shown that urine is not sterile, and it is becoming clear that the urine microbiota of patients with BC and in healthy individuals differs. The project plans to investigate three important elements of the relationship between microbiota and bladder cancer. First, we will investigate changes in the composition of the urine microbiota during the treatment of bladder cancer with BCG immunotherapy. Although BCG was introduced more than 40 years ago, the mechanism of its action is not entirely clear. Most studies have investigated the response of immune and urothelial cells during BCG treatment, while the bladder microbiota has been largely neglected. Therefore, we plan to monitor changes in the urinary microbiota in patients during BCG treatment and to link these changes to tumor recurrence. Second, mice with the dysfunctional molecule TLR4, which is a receptor for Gram-negative bacteria (such as Escherichia coli and Fusobacterium nucleatum), will examine the role of TLR4 as well as the potential role of Gram-negative bacteria in bladder cancer. Third, by induction of BC In germ free mice, we will study the overall contribution of the whole microbial community to the development of BC. By studying patients with bladder cancer and mouse models for the disease, the proposed project seeks to identify important aspects of the role that microbiota play in the development and recurrence of BC. Identification of microbes or microbial-related molecular elements important for BC pathology would open up new possibilities in diagnosis as well as in the prevention and treatment of bladder cancer.

Relevant publications: 

- DNA Methylome Changes of Muscle- and Neuronal-Related Processes Precede Bladder Cancer Invasiveness. Bošković M, Roje B, Chung FF, Gelemanović A, Cahais V, Cuenin C, Khoueiry R, Vilović K, Herceg Z, Terzić J. Cancers (Basel). 2022 Jan 19;14(3):487. doi: 10.3390/cancers14030487.
- Stat3 signalling is essential for bladder cancer progression. Korac-Prlic J, Degoricija M, Vilović K, Ivanisević T, Haupt B, Franković L, Grivennikov S, Terzić J. Cancer Letters 490, 2020, 89–99. doi: 10.1016/j.canlet.2020.06.018. IF 7,36
- Microbiota Alters Urinary Bladder Weight and Gene Expression. Roje B, Elek A, Palada V, Bom J, Iljazović A, Šimić A, Sušak L, Vilović K, Strowig T, Vlahoviček K, Terzić J. Microorganisms. 2020 Mar 17;8(3):421. doi: 10.3390/microorganisms8030421. IF 4,167
- Vitamin A enriched diet diminishes early urothelial carcinogenesis. Korac-Prlic J*, Zupančič D*, Erdani Kraft M, Frankovic L, Vilovic K, Jeruc J, Romih R, Terzić J. Cancers (Basel) 12, 2020, 1712. doi: 10.3390/cancers12071712. IF 6,126
- The dynamics of the inflammatory response during BBN-induced bladder cancerogenesis in mice. Degoricija M, Korac-Prlic J, Vilovic K, Ivanisević T, Haupt B, Palada V, Petković M, Karaman I, Terzić J. Journal of Translational Medicine 17, 2019, 394 doi: 10.1186/s12967-019-02146-5. IF 4,124
- The urinary microbiome associated with bladder cancer. Bučević Popović V, Šitum M, Chow CT, Chan LS, Roje B, Terzić J. Sci Rep. 2018 Aug 14;8(1):12157. doi: 10.1038/s41598-018-29054-w. IF 4,011

Role of inflammation in bladder cancer pathogenesis - iBC

(HRZZ Research project)

Project leaderprof. dr. sc. Janoš Terzić

Project timeframe: 28.10.2015.- 27.10.2019.

Blanka Roje, mag. educ. biol. et chem. - PhD student Marina Degoricija
prof. dr. sc. Marijan Šitum 

prof. dr. sc. Ivan Đikić, Goethe University School of Medicine, Frankfurt am Main, Germany
prof. dr. sc. Sergei Grivennikov, Fox Chase Cancer Center, Philadelphia, USA

Project summary:
Around 20% of cancer deaths are a consequence of chronic inflammation. Viral and bacterial infections, parasitic infestation, autoimmunity or chemical irritants cause inflammatory changes that stimulate cancer initiation, promotion and metastasis. We and others have shown that main molecular links between inflammation and cancer are cytokine IL-6 and its transcription factor STAT3. It is becoming obvious that microbiome composition of particular niche is important element of inflammation and cancer development. The role of inflammation in urinary bladder cancer (BC) pathogenesis is poorly understood although chronic inflammation caused by Schistosoma haematobioum has pro-tumorigenic effect while acute inflammation induced by BCG is successfully used as a therapy for BC. 
This project addresses fundamental questions of bladder cancerogensis. If altering STAT3 activity has inhibitory effect on BC development that finding can lead to new therapies (use of STAT3 inhibitors) for established BC. Findings generated by the microbiome analysis can lead to novel preventive measures (microbiota manipulation by antibiotics or vaccination). 
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