The 8th International Conference on Biomedical Engineering and Biotechnology (ICBEB 2019)
October 22-25, 2019, Seoul, Republic of Korea
Invited Speaker--Dr. Sebastian Oltean

Senior Lecturer, Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, UK

Sebastian studied clinical medicine at "Iuliu Hatieganu" Medical School, Cluj-Napoca, Romania and trained as a junior doctor in Nephrology and Dialysis before moving to USA where he obtained a PhD from the University of Nebraska-Lincoln in 2004.This was followed by postdoctoral training at Duke University Medical Center (North Carolina, USA) where he became interested in studying the connections between alternative splicing and cancer. In 2008 he moved to the University of Bristol where he continued to study alternative splicing in vivo, with focus towards the importance of several genes splice isoforms (e.g VEGF, FGFR2) in cancer as well as kidney diseases and development of splice-based therapeutics. In 2012 he was appointed independent research fellow and principal investigator and developed his own research group in Bristol before moving to University of Exeter Medical School in 2017

Speech Title: Modulators of alternative splicing as novel therapeutics in cancer

Background: The epithelial-mesenchymal transition (EMT), one of the hallmarks of cancer, is a biological process involving a functional transition of polarized epithelial cells into mobile mesenchymal cells. Epithelial splicing regulatory proteins 1 and 2 (ESRP1 and 2) are cell-type-specific regulators of transcripts that switch splicing during the EMT. ESRPs drive splicing events of about 200 genes that define the epithelial phenotype. One of the well-known genes regulated by ESRPs is fibroblast growth factor receptor 2 (FGFR2) which has a switch between two mutually exclusive isoforms - FGFR2-IIIb and FGFR2-IIIc during the EMT. Previous studies established ESRPs as master regulators of EMT and underlie EMT during tumour progression. In this study we wanted to explore the role of ESRPs in prostate cancer and to screen for compounds that may reverse EMT by modulating alternative splicing.

Methods: To explore ESRPs’ functions in tumours we constructed stable PC3 cell lines overexpressing either ESRP1, or ESRP2, or both ESRP1 and 2. In vivo, we grew xenografts in nude mice and monitored the tumour size. In vitro, we carried out a set of functional assays (cell growth, EMT markers, cell migration).
As FGFR2 splicing is a sensor of ESRPs activity and EMT, we used a splicing-sensitive fluorescent reporter based on inclusion/exclusion of FGFR2 exon IIIc to perform a screen. This was done with the LOPAC library (Library of Pharmacologically Active Compounds) on HEK293 cells to identify compounds that induce skipping of exon IIIc in FGFR2 and potentially block EMT.

Results: We have found that ESRP1 and 2 decrease tumour growth in vivo, decrease cell growth, affect EMT - induce E-cadherin, and do not affect cell migration in vitro.
We have identified several compounds that switch FGFR2 splicing, which validated as modulators of EMT and showed various activities in functional assays in vitro. One of this compounds decreases tumour growth in vivo upon intraperitoneal administration in nude

Conclusion: ESRPs have tumour suppressors functions in prostate cancer. Small molecule modulators of alternative splicing, that may or may not work through ESRPs, have the potential to form novel anti-tumour therapeutics by inhibiting EMT.

The 8th International Conference on Biomedical Engineering and Biotechnology
Conference Secretaries: Ms. Linda Li, Ms. Annie Zhu, Ms. Cassie Cheng
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