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The role of long non-coding RNA regulatory networks in pancreatic cancer

  • School: School of Science and Technology
  • Study mode(s): Full-time / Part-time
  • Starting: 2023
  • Funding: UK student / EU student (non-UK) / International student (non-EU) / Fully-funded

Overview

NTU's Fully-funded PhD Studentship Scheme 2023

Project ID: S&T3

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of approximately 11%. This is mainly due to late detection, early metastasis and resistance to treatments. Thus, there is an urgent need to elucidate the molecular mechanism of this cancer and identify new therapeutic options.

Transforming growth factor beta (TGF-β) signaling plays a crucial role in PDAC development. During the advanced stages of the disease TGF-β acts as an oncogene, promoting epithelial-to-mesenchymal transition (EMT), tumourigenesis and metastasis.

Our laboratory is interested in studying the role of a class of molecules called non-coding RNAs (ncRNAs). These molecules play a vital role in the development of cancer and can be used as therapeutic targets or biomarkers. Our particular focus is on microRNAs (miRNAs) and long ncRNAs (lncRNAs) in the advanced stages of pancreatic cancer.

We have previously profiled miRNAs that are regulated by TGF-β and shown that two specific miRNAs, miR-100 and miR-125b, are up-regulated by TGF-β and act as oncogenic miRNAs in PDAC (Ottaviani et al Nat Commun. 2018). Specifically, these miRNAs promote TGF-β-mediated functions including EMT and cancer stem cells formation. In addition, upon silencing they inhibit metastatic spread in vivo. Our latest results based on RNA-seq and ChIP-seq revealed the lncRNAs upregulated by TGF-β that are also directly regulated by SMAD2/3 transcription factors. However, their function in the development of PDAC has not been elucidated.

In this project we aim to:

1.Identify the mechanism of action of lncRNAs in TGF-β signaling

The first step in the understanding of the mechanism of action of lncRNAs is the evaluation of their cellular localisation. We will define this by cell fractionation as well as RNA-FISH. To investigate the role of lncRNAs in TGF-β signaling we will establish a KO using CRISPR/Cas9 and investigate whether the KO affects the expression of TGF-β target genes by RNA-seq. We will also evaluate the effect of the KO on TGF-β-mediated EMT, cell motility/invasion, stemness and resistance to chemotherapeutic drugs. Importantly, growth assays will be performed in 3D organoid models, as a clinically relevant model that recapitulate pancreatic cancer.

2.Establish the clinical relevance of TGF-β-regulated lncRNAs

Bioinformatic analysis of “big data” (RNA-seq, single-cell RNA-seq, spatial transcriptomics) on pancreatic cancer patients will be performed to link basic research to translational/clinical outcome. Furthermore, we aim to use RNAscope to detect lncRNA expression in cancer patients. Ultimately, with this project we aim to investigate candidate lncRNAs as new therapeutic targets for PDAC.

Supervisory Team:

Supervisor:

Dr Silvia Ottaviani: Senior Lecturer in Molecular Cell Biology at NTU and Honorary Lecturer at Imperial College London.

Co-Supervisors:

Dr Christos Polytarchou: Associate Professor, NTU

Dr Daniel D’Andrea: Lecturer in Bioinformatics, NTU

Entry qualifications

For the eligibility criteria, visit our studentship application page.

How to apply

To make an application, please visit our studentship application page.

Fees and funding

This is part of NTU's 2023 fully-funded PhD Studentship Scheme.

Guidance and support

Application guidance can be found on our studentship application page.

Still need help?

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