Lea Duwe

Name: Lea Duwe

Nationality: German

Academic Background: Bachelor of Science degree in Chemistry and Biochemistry, Ludwigs-Maximilians University Munich Master of Science degree in Biochemistry, University of Leipzig

Project Title: Impact of deregulated microRNAs on chemoresistance in cholangiocarcinoma

Project Background:  Cholangiocarcinoma (CCA) is a severe malignancy in the bile ducts. Despite being a relative rare cancer type, its incidence and mortality rates are increasing. Current chemotherapy regimens are palliative, as such the only curative treatment options are surgery and liver transplantation. The lack of effective therapy may be explained by mechanisms of resistance cancer cells develop to drugs. In this regard, aberrant expression of microRNAs (miRs) are linked to CCA development and drug resistance. MiRs are short non-coding RNAs, which can inhibit the stability and translation of their target genes. The role of miRs in cancer is complex, as a single miR can bind to and inhibit many genes, and therefore may affect entire signaling networks. However, this consequence of miR-gene regulation may also represent a novel opportunity in therapeutics, in which targeting a single miR can `correct´ an entire perturbed signaling pathway. Therefore, it is vital to elucidate the biological function of specific miRs in the right context (cell type, organ, organism) to elucidate which key chemoresistance pathways are altered. In this project, I hypothesize that key miRs have a causal role in modifying drug resistance in CCA. Interestingly, the initial analysis suggested an involvement of the cilium as a mechanism for resistance. Cilia are antenna-like organelles, which can sense the chemical composition of the bile. Also, it is intriguing that this chemosensory organelle is lost in malignant cholangiocytes. Therefore, I aim focusing on the aberrant cilium-dependent signaling as an important player of chemoresistance in CCA.

Project Aim:  I will 1) characterize the role of specific miRs in cancer-related phenotypes, 2) characterize their role in drug resistance, and 3) analyze the biological impact of key miRs regulating drug response(s). I will select one miR to emphasize its biological role in mediating chemoresistance in CCA.

Expected Outcome:  The results of this project will reveal new molecular mechanism(s) of resistance in CCA and may pave the way for miR-based therapies. This project comprises comprehensive data from tumor tissues, patient-derived primary cell cultures and in vivo xenograft models. It is designed as an interdisciplinary translational study to investigate options to evade drug resistance in CCA patients with the goal to improve quality of life for cholangiocarcinoma patients.

Contact: lea.duwe@bric.ku.dk