Epigenetic alterations in oesophageal carcinoma: The role of microRNAs in determination and prediction of chemo- and radiosensitivity in oesophageal cancer and its meaning for response control of neoadjuvant therapy
Final Report Abstract
The current scholarship provided the unique opportunity for the applicant to work in the highly experienced and efficient Upper GI Laboratory of the Surgical Department at Flinders University/Adelaide/Australia. Based on the excellent support of the team in Adelaide, the applicant was able to work successfully on all parts of his project. We could finally answer all hypotheses formulated in the initial proposal despite of the limitation to only investigate miRNAs in the context of chemotherapy in oesophageal cancer. Especially the adaptation of the research programme, which was mainly based on the experience of our partners in the respective research fields, allowed a more detailed analysis of the primary questions. Taken together, we were able to generate the initially mentioned molecular database that provides a number of miRNAs which potentially play a crucial role in chemotherapy response and resistance in oesophageal cancer. We could show in in-vitro and in-vivo experiments that miRNA profiling is indeed an adequate tool to determine and predict chemo-sensitivity in oesophageal adenocarcinoma and squamous cell carcinoma. Furthermore, we confirmed that chemotherapy itself affects miRNA expression in cell culture experiments implicating that miRNA expression profiling is as well an adequate tool to monitor the success of neoadjuvant treatment of oesophageal tumours. In addition, we identified several intracellular pathways such as KRAS or others which are deregulated in drug resistant cells highlighting these pathways as potential targets of the identified deregulated miRNAs in these resistant cell lines. Finally, we demonstrated in a first project that ectopic miRNA modulation impacts on the oesophageal cancer cells’ response to cisplatin and 5-FU. This part supports the emerging role of miRNAs in new therapeutic approaches in the battle against oesophageal cancer. And thirdly, the extension of the initial research programme and the inclusion of several new techniques such as work with tumor-derived exosomes finally led to the chance for the applicant to prepare his further research work in Germany. The expertise in these additional techniques, which were not primarily necessary to answer the questions formulated in the initial proposal, allowed the development of a profound follow-up research programme.
Publications
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Impact of miRNAs on sensitivity to anticancer treatment in sensitive and resistant esophageal squamous cell carcinoma cell lines. 12th World Congress Of The International Society For Diseases Of The Esophagus (ISDE), Kagoshima, Japan, September 2-5, 2010. Published: Dis Esophagus. 2010 Aug;23 (Suppl 1):48A-49A
R Hummel, DI Watson, C Smith, J Kist, MZ Michael, M Bruewer, J Haier, DJ Hussey
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MicroRNAS Predict Staging And Outcome in Patients With Locally Advanced Esophageal Cancer. Royal Australasian College of Surgeons Annual Scientific Congress, 4-7 May 2010, Perth, Western Australia. Published: ANZ J. Surg. 2010; 80 (Suppl. 1) A87
R Hummel, DJ Hussey, MZ Michael, M Bruewer, J Haier, DI Watson
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MicroRNAs: Expressionsanalysen verbessern das Staging bei Patienten mit lokal fortgeschrittenem Ösophaguskarzinom. 127. Kongress der Deutschen Gesellschaft für Chirurgie. Berlin, 20.- 23.04.2010. Düsseldorf: German Medical Science GMS Publishing House; 2010
R Hummel, DJ Hussey, MZ Michael, M Brüwer, J Haier, D Palmes, DI Watson
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MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer. 2010 Jan;46(2):298-311
Hummel R, Hussey DJ, Haier J
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MiRNAs improve response to chemotherapy in esophageal cancer. 5th Australian Health & Medical Research (AHMRC) Congress 2010, 14th November - 18th November
R Hummel, DI Watson, C Smith, J Kist, MZ Michael, M Bruewer, J Haier, DJ Hussey
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MiR-148a improves response to chemotherapy in sensitive and resistant esophageal adeno and squamous cell carcinoma cells. J Gastrointest Surg. 2011 (B) Mar;15(3):429-38. Epub 2011 Jan 19
Hummel R, Watson DI, Smith C, Kist J, Michael MZ, Haier J, Hussey DJ
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MiRNAs and Their Association with Locoregional Staging and Survival Following Surgery for Esophageal Carcinoma. Ann Surg Oncol. 2011 (A) Jan;18(1):253-60. Epub 2010 Jul 14
Hummel R, Hussey DJ, Michael MZ, Haier J, Bruewer M, Senninger N, Watson DI
