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Dr S Schlopp
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
About
Supervisory Team: Dr Steffen Scholpp
Location: Exeter, Streatham Campus
Project
The gastrointestinal epithelium is strongly dependent on the balance between cell proliferation, cell cycle arrest, and cell migration. The Wnt signalling network plays a crucial role in regulating these processes in several organs, but it’s role in the gastric mucosa is poorly understood. The canonical Wnt/β-catenin branch is activated in more than 30% of gastric cancer tissues leading to the upregulation of several components of the Wnt pathways such as effectors of the actin cytoskeleton.
Furthermore, Wnt/β-catenin signalling is essential for the self-renewal of gastric cancer stem cells leading to Wnt-mediated resistance to apoptosis, which may explain the increasing number of recurrence of these primary tumours. The non-canonical, β-catenin independent branch plays a similarly important role. The non-canonical key ligands, such as Wnt5a, are upregulated in gastric cancer regardless of the histological phenotype and are correlated with poor prognosis. It is unknown how these signalling branches cooperate during gastric carcinogenesis.
Recent evidence from the Scholpp lab suggested that canonical Wnt ligands are loaded on and distributed by signalling filopodia in vertebrate tissue (Stanganello et al., 2015). The generation and dynamic of Wnt filopodia is regulated by components of the non-canonical Wnt signalling pathway. In independent studies, the Scholpp, Dale & Phesse labs demonstrated that the Wnt receptor Fzd7 modulates the transmission of both canonical and non-canonical Wnt pathways (Phesse et al., 2016; Brinkmann et al., 2016), and is upregulated in gastric tumours (Flanagan et al., 2017). Preliminary data suggest that Fzd7 is a crucial regulator of signalling filopodia length in cell culture and in the zebrafish vertebrate model organism. Furthermore, Fzd7 is localised together with the Wnt ligands at the signalling filopodia tips. At this point, we hypothesize that non-canonical Wnt signalling via Fzd7 activation regulates Wnt transport by stimulating Wnt filopodia formation. Consistently, Wnt mediated activation of Fzd7 promotes cell proliferation and the growth of gastric tumour organoids.
In this project, we aim to decipher the function of Fzd7 in regulating Wnt transport. The student will analyse Wnt transport in gastric cancer organoids (Jardé et al., 2016; Flanagan et al 2016, 2017) and in-vivo inzebrafish models (Hagemann et al., 2014; Stanganello et al., 2015). The student will use high-resolution imaging to describe the dynamic of Wnt transport in these tissues. The student will then alter cytoneme-based Wnt transport by regulating Fzd7 activity. Complementary to the genetic approach, the student will test approved cancer drugs - specifically cytoskeletal modulators - for their function on cytoneme-based transport of Wnt signals in the gastric cancer stem cell niche.
Start date: October 2018
Most studentships will be 3.5 years full time or up to 7 years part-time, and can be longer where additional training is undertaken.
How to apply
APPLICATIONS OPEN ON 25 SEPTEMBER AND CLOSE AT 17:00 ON 24 NOVEMBER 2017.
IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form. More information on the application process may be found here: http://www.gw4biomed.ac.uk/projects-2/for-students/
You do NOT need to apply to the University of Exeter at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Exeter.
Supervisory Team: Dr Steffen Scholpp
Location: Exeter, Streatham Campus
Project
The gastrointestinal epithelium is strongly dependent on the balance between cell proliferation, cell cycle arrest, and cell migration. The Wnt signalling network plays a crucial role in regulating these processes in several organs, but it’s role in the gastric mucosa is poorly understood. The canonical Wnt/β-catenin branch is activated in more than 30% of gastric cancer tissues leading to the upregulation of several components of the Wnt pathways such as effectors of the actin cytoskeleton.
Furthermore, Wnt/β-catenin signalling is essential for the self-renewal of gastric cancer stem cells leading to Wnt-mediated resistance to apoptosis, which may explain the increasing number of recurrence of these primary tumours. The non-canonical, β-catenin independent branch plays a similarly important role. The non-canonical key ligands, such as Wnt5a, are upregulated in gastric cancer regardless of the histological phenotype and are correlated with poor prognosis. It is unknown how these signalling branches cooperate during gastric carcinogenesis.
Recent evidence from the Scholpp lab suggested that canonical Wnt ligands are loaded on and distributed by signalling filopodia in vertebrate tissue (Stanganello et al., 2015). The generation and dynamic of Wnt filopodia is regulated by components of the non-canonical Wnt signalling pathway. In independent studies, the Scholpp, Dale & Phesse labs demonstrated that the Wnt receptor Fzd7 modulates the transmission of both canonical and non-canonical Wnt pathways (Phesse et al., 2016; Brinkmann et al., 2016), and is upregulated in gastric tumours (Flanagan et al., 2017). Preliminary data suggest that Fzd7 is a crucial regulator of signalling filopodia length in cell culture and in the zebrafish vertebrate model organism. Furthermore, Fzd7 is localised together with the Wnt ligands at the signalling filopodia tips. At this point, we hypothesize that non-canonical Wnt signalling via Fzd7 activation regulates Wnt transport by stimulating Wnt filopodia formation. Consistently, Wnt mediated activation of Fzd7 promotes cell proliferation and the growth of gastric tumour organoids.
In this project, we aim to decipher the function of Fzd7 in regulating Wnt transport. The student will analyse Wnt transport in gastric cancer organoids (Jardé et al., 2016; Flanagan et al 2016, 2017) and in-vivo inzebrafish models (Hagemann et al., 2014; Stanganello et al., 2015). The student will use high-resolution imaging to describe the dynamic of Wnt transport in these tissues. The student will then alter cytoneme-based Wnt transport by regulating Fzd7 activity. Complementary to the genetic approach, the student will test approved cancer drugs - specifically cytoskeletal modulators - for their function on cytoneme-based transport of Wnt signals in the gastric cancer stem cell niche.
Start date: October 2018
Most studentships will be 3.5 years full time or up to 7 years part-time, and can be longer where additional training is undertaken.
How to apply
APPLICATIONS OPEN ON 25 SEPTEMBER AND CLOSE AT 17:00 ON 24 NOVEMBER 2017.
IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form. More information on the application process may be found here: http://www.gw4biomed.ac.uk/projects-2/for-students/
You do NOT need to apply to the University of Exeter at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Exeter.
Funding Notes
Stipend matching UK Research Council National Minimum (£14,553 p.a. for 2017/18, updated each year) plus UK/EU tuition fees
UK and EU applicants who have been residing in the UK since September 2015 will be eligible for a full award; those who do not meet this residency requirement may be eligible for a fees-only award.
Applicants who are classed as International for tuition fee purposes are not eligible for funding.
UK and EU applicants who have been residing in the UK since September 2015 will be eligible for a full award; those who do not meet this residency requirement may be eligible for a fees-only award.
Applicants who are classed as International for tuition fee purposes are not eligible for funding.
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