The role of Eps8 in regulating pancreatic cancer invasion
Lead Research Organisation:
University of Southampton
Department Name: Cancer Sciences
Abstract
The spread of malignant cells locally (tumour invasion) is fundamental to cancer development and progression. Pancreatic adenocarcinoma (PAC) has one of the worst outcomes of any cancer; only 3% of patients survive for 3 years, and 50% of patients die within 6 months. Less than 20% of patients are suitable for surgical treatment, and this is because, by the time that PAC is diagnosed, it has spread into adjacent tissues, making surgery impossible.
We, and others, have shown that the proteins Eps8 and integrin v 6 are upregulated in a number of different cancer types, including PAC. More recently, we have shown a link between Eps8 and v 6 in regulating the movement of pancreatic cancer cells, although we have not yet identified the mechanism(s) controlling the invasive process. The aim of this study is to determine how the two proteins interact to promote PAC cell movement.
Understanding this process will give crucial insight into the biology of tumour cell invasion, and may uncover novel targets for the treatment and/or prevention of PAC
We, and others, have shown that the proteins Eps8 and integrin v 6 are upregulated in a number of different cancer types, including PAC. More recently, we have shown a link between Eps8 and v 6 in regulating the movement of pancreatic cancer cells, although we have not yet identified the mechanism(s) controlling the invasive process. The aim of this study is to determine how the two proteins interact to promote PAC cell movement.
Understanding this process will give crucial insight into the biology of tumour cell invasion, and may uncover novel targets for the treatment and/or prevention of PAC
Technical Summary
Background: Pancreatic adenocarcinoma has one of the worst prognoses of any cancer, with a 5-yr survival rate of 3% and a median survival of <6 months. Less than 20% of patients present with localised disease treatable by surgery, and even then, 5-year survival remains low (20%)1. It is clear that new molecular-based treatments are required
Eps8 is a multifunctional protein, central to actin cytoskeletal reorganisation. Although the biochemistry of Eps8 has been investigated, its regulation and functional role in cells is less well understood, particularly in tumours. Recently we identified a functional link between tumour motility, Rac1 activation and Eps8. This was the first study showing that Eps8 can regulate collective tumour invasion in a physiologically relevant 3-D assay.
Preliminary data: Our preliminary unpublished data show that Eps8 promotes PAC cell motility, and this is modulated through the integrin v 6, which is upregulated in numerous carcinomas, particularly PAC, where over 60% of tumours express the integrin strongly. We were the first to show that ?v?6 promotes tumour invasion, and further discovered that this process is modulated through activation of the small GTP-ase, Rac1, and requires integrin internalisation. Since Eps8 regulates GTP-ase activation, actin reorganisation and receptor endocytosis, ii may be of central importance in modulating v 6-dependent cell functions
Aims: The aim of this project is to determine the mechanism(s) by which Eps8 links integrin signalling, regulation of the actin cytoskeleton and cell function.
Objectives and methodology: We will examine the expression and distribution of Eps8, and ?v?6 in human PAC, and relate these findings to disease development and progression. We will identify the Eps8 binding partners in PAC cells, before dissecting the mechanism(s) by which Eps8 modulates ?v?6-dependent invasion: specifically examining its role in GTP-ase activation, integrin endocytosis and integrin-dependent TGF- 1 activation. The effect of Eps8-dependent actin bundling and capping on PAC invasion will also be examined. Finally we will use PAC models to examine the functional role of the Eps8/ ?v?6 axis in vivo.
Scientific and medial opportunities: This study may uncover novel targets for the treatment and/or prevention of PAC, and will also give crucial insight into the general biology of tumour cell invasion.
Eps8 is a multifunctional protein, central to actin cytoskeletal reorganisation. Although the biochemistry of Eps8 has been investigated, its regulation and functional role in cells is less well understood, particularly in tumours. Recently we identified a functional link between tumour motility, Rac1 activation and Eps8. This was the first study showing that Eps8 can regulate collective tumour invasion in a physiologically relevant 3-D assay.
Preliminary data: Our preliminary unpublished data show that Eps8 promotes PAC cell motility, and this is modulated through the integrin v 6, which is upregulated in numerous carcinomas, particularly PAC, where over 60% of tumours express the integrin strongly. We were the first to show that ?v?6 promotes tumour invasion, and further discovered that this process is modulated through activation of the small GTP-ase, Rac1, and requires integrin internalisation. Since Eps8 regulates GTP-ase activation, actin reorganisation and receptor endocytosis, ii may be of central importance in modulating v 6-dependent cell functions
Aims: The aim of this project is to determine the mechanism(s) by which Eps8 links integrin signalling, regulation of the actin cytoskeleton and cell function.
Objectives and methodology: We will examine the expression and distribution of Eps8, and ?v?6 in human PAC, and relate these findings to disease development and progression. We will identify the Eps8 binding partners in PAC cells, before dissecting the mechanism(s) by which Eps8 modulates ?v?6-dependent invasion: specifically examining its role in GTP-ase activation, integrin endocytosis and integrin-dependent TGF- 1 activation. The effect of Eps8-dependent actin bundling and capping on PAC invasion will also be examined. Finally we will use PAC models to examine the functional role of the Eps8/ ?v?6 axis in vivo.
Scientific and medial opportunities: This study may uncover novel targets for the treatment and/or prevention of PAC, and will also give crucial insight into the general biology of tumour cell invasion.