E-Cadherin Endocytosis In Morphogenesis: Recycling And Growth Factor Induced Uptake.
Funder
National Health and Medical Research Council
Funding Amount
$498,088.00
Summary
E-cadherin is a cell-cell adhesion protein expressed in all epithelia with essential roles in establishing cell polarity and in tissue patterning during development. In the adult, E-cadherin functions to maintain epithelial integrity. E-cadherin is also a vital tumour suppressor, protecting cells against metastatic transformation. Our earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. The endocytosis or internalisation of cell ....E-cadherin is a cell-cell adhesion protein expressed in all epithelia with essential roles in establishing cell polarity and in tissue patterning during development. In the adult, E-cadherin functions to maintain epithelial integrity. E-cadherin is also a vital tumour suppressor, protecting cells against metastatic transformation. Our earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. The endocytosis or internalisation of cell surface E-cadherin serves to regulate its role in adhesion. More recently, we and others have shown that E-cadherin is endocytosed in response to growth factors, in conjunction with the activated growth factor receptors themselves. E-cadherin can influence the trafficking and signaling of these receptor tyrosine kinases. This joint endocytosis is an elegant mechanism for the simultaneous downregulation of cell adhesion and activation of signaling for cell growth and motility. The growth and differentiation of epithelial cells during tissue patterning or morphogenesis relies critically on these endocytic pathways. Our research is aimed at defining the endosomes and cellular machinery involved in E-cadherin-receptor endocytosis, moreover we will pursue initial findings suggesting that there are different pathways and fates for E-cadherin endocytosed at the behest of different growth factors. We will study endocytosis during the processes of epithelial cyst formation and tubulation of cysts as an in vitro model for mammalian morphogenesis. These studies will provide important and novel information for understanding the roles of E-cadherin in adhesion and in growth factor signaling during epithelial morphogenesis. Ultimately these findings will be of relevance to epithelial development and the prevention of cancer.Read moreRead less
Exploring The Function Of Breast Cancer-Associated Variants In Long Non-Coding RNAs
Funder
National Health and Medical Research Council
Funding Amount
$501,585.00
Summary
Recent studies have identified regions within the human genome in which DNA sequence variations are associated with an increased risk of breast cancer. Several of these regions do not contain any known protein coding genes, suggesting that non-protein coding genes could be responsible for the associated risk. The aim of this proposal is to identify and characterise these non-coding genes. Understanding how sequences variations in these novel genes contribute to breast cancer will provide novel a ....Recent studies have identified regions within the human genome in which DNA sequence variations are associated with an increased risk of breast cancer. Several of these regions do not contain any known protein coding genes, suggesting that non-protein coding genes could be responsible for the associated risk. The aim of this proposal is to identify and characterise these non-coding genes. Understanding how sequences variations in these novel genes contribute to breast cancer will provide novel avenues for therapy.Read moreRead less
Recycling Endosomes Governing Cell Polarity And Cytokine Secretion.
Funder
National Health and Medical Research Council
Funding Amount
$958,412.00
Summary
Cytokines are chemical messengers released by cells to mount inflammatory responses to fight infections. The timing and direction of cytokine release must be tightly regulated. We investigate the cellular compartments and molecules that control cytokine secretion using sophisticated live cell imaging. Uncontrolled cytokine release is the main cause of ongoing inflammation in arthritis and inflammatory bowel disease and our studies aim to identify cellular targets for new drug development.
Identifying Novel Long-noncoding RNAs Involved In The Development Of Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$785,204.00
Summary
Recent studies have identified regions within the human genome in which DNA sequence variations are associated with an increased risk of breast cancer. The aim of this proposal is to identify and characterise these non-coding genes that are modulate breast cancer risk. Understanding how sequences variations that alter these novel genes contribute to breast cancer will provide novel avenues for therapy.
We have identified genetic abnormalities in 5% of breast cancers that fall in a novel DNA element called BIME1. This proposal aims to determine whether these genetic abnormalities contribute to breast tumourigenesis and which genes and pathways are affected by these mutations. The outcomes of this proposal may lead to the development of novel therapies for breast cancer or could influence the choice of existing therapies for patients that harbour these genetic abnormalities.
Psychosocial Aspects Of Genomic Testing For Breast Cancer Risk
Funder
National Health and Medical Research Council
Funding Amount
$108,902.00
Summary
Assessing a woman’s breast cancer risk by profiling polygenic risk represents a new approach in the familial cancer setting. My study is part of a program of research that aims to facilitate translation of polygenic risk information into clinical practice. For this, I will invite 400 women to receive their personal polygenic result and i) assess interest in receiving this result; ii) assess psychological and behavioural outcomes of receiving or not receiving their personal polygenic risk result
Activation Of TERT Gene Expression In Breast Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$693,440.00
Summary
A key step in the development of most cancers is the switching on of an enzyme, telomerase, that allows cancer cells to keep growing without limit. We will study the molecular details of this step using new techniques for functional analyses of the genome in human breast cells grown in the laboratory. Blocking telomerase has great potential for cancer treatment, so analysing how this enzyme gets switched on may identify new strategies for achieving this for breast cancer - and other cancers.
Functional Analysis Of Breast Cancer Susceptibility Regions
Funder
National Health and Medical Research Council
Funding Amount
$790,588.00
Summary
Recent studies have identified regions within the human genome in which DNA sequence variations are associated with an increased risk of breast cancer. Several of these regions do not contain any known genes, suggesting that regulatory DNA sequences are responsible for the associated risk. The aim of this proposal is to identify and characterise these DNA sequences. Understanding how sequences variations in these regions contribute to breast cancer will provide novel avenues for therapy.
High-throughput Identification And Evaluation Of New Breast Cancer Genes From GWAS.
Funder
National Health and Medical Research Council
Funding Amount
$841,075.00
Summary
Recent studies have identified DNA markers within the human genome that are associated with an increased risk of breast cancer. Most of these markers are located in noncoding regions, therefore the key genes driving risk are not known. This proposal will identify the target genes at all breast cancer risk regions and assess how specific markers affect disease risk. Understanding how DNA variation contributes to breast cancer will provide new avenues for prevention or treatment.
Polarized Trafficking Of E-cadherin In Epithelial Cells.
Funder
National Health and Medical Research Council
Funding Amount
$515,564.00
Summary
The cell adhesion protein E-cadherin is expressed in all epithelial tissues of the body where it has essential functions during development and in the adult in establishing and maintaining polarized cell monolayers. E-cadherin is also a vital tumour suppressor, its normal function guarantees that cells or even early tumours cannot metastasise; in contrast E-cadherin is always lost or malfunctions in malignant tumours. Earlier studies showed that E-cadherin is constantly moved, or trafficked, to ....The cell adhesion protein E-cadherin is expressed in all epithelial tissues of the body where it has essential functions during development and in the adult in establishing and maintaining polarized cell monolayers. E-cadherin is also a vital tumour suppressor, its normal function guarantees that cells or even early tumours cannot metastasise; in contrast E-cadherin is always lost or malfunctions in malignant tumours. Earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. This trafficking has dual roles, firstly in delivering newly-made E-cadherin to the surface where it functions and secondly, in regulating its adhesive function. Our research in this project is focussed on the molecules and intracellular compartments that control the delivery of E-cadherin to the cell surface. E-cadherin must be sorted in order to be delivered to the correct side of the cell. Having previously discovered the sorting signal in E-cadherin, we will now identify the cognate adaptor protein(s) that accomplish this sorting. New imaging techniques allow us to study protein trafficking inside live cells. Such studies have recently revealed that E-cadherin passes through a recycling endosome compartment on its way to the cell surface. This unexpected route, and the structure and role of the recycling endosome will now be studied in detail in live cells. Finally we will compare the sorting and trafficking of E-cadherin with the closely-related N-cadherin protein, to determine whether there are inherent differences in their trafficking that could explain their opposite roles in tumour cells, where N-cadherin is substituted for E-cadherin and allows metastatic behaviour. These studies will provide important information for understanding the adhesive and tumour suppressive roles of E-cadherin. In addition our findings will generate information fundamental to our understanding of cell polarity and protein sorting.Read moreRead less