Characterisation Of Cooperation Between Cell Polarity Regulators And Oncogenes In Tumourigenesis Using Drosophila
Funder
National Health and Medical Research Council
Funding Amount
$304,773.00
Summary
Cancers affect 1-3 people at some stage during their lifetime and therefore is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. In addition, recent studies have shown that the tumour environment (the interaction between cells) can be a major factor in the development of the cancer. However, this is difficult to study in mammalian models. In this proposal we use t ....Cancers affect 1-3 people at some stage during their lifetime and therefore is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. In addition, recent studies have shown that the tumour environment (the interaction between cells) can be a major factor in the development of the cancer. However, this is difficult to study in mammalian models. In this proposal we use the genetically amenable, model system, the vinegar fly Drosophila, to investigate the development of tumours using defined mutations. To explore mechanisms of tumourigenesis in Drosophila, we are using a system where we can make patches (clones) of mutant tissue within the context of normal tissue, a system that more faithfully mimics the development of mammalian cancer. We have observed that certain genes required for cell shape, (cell polarity genes, such as scrib) are important in limiting the action of oncogenes (tumour- causing genes, such as activated alleles of Ras) in the development of tumours in Drosophila. Thus, mutants in cell polarity genes cooperate with oncogenic mutations to result in the generation of invasive tumours. In a genetic screen, we have identified further genes that act in a similar manner to cooperate with mutants in scrib or activated Ras. In this proposal we seek to characterise these genes in tumourigenesis and to explore their mechanism of action. The expected outcome of this project is to elucidate novel genes and mechanisms of tumourigenesis in the context of a whole organism. Due to the conservation of cell proliferation and signalling proteins, this proposal is relevant to understanding human cancer.Read moreRead less
Analysis Of Rho GTPase Signalling Pathways In An Epithelial To Mesenchymal Transition During Development Of The Mesoderm
Funder
National Health and Medical Research Council
Funding Amount
$409,500.00
Summary
A critical step in the progression of cancers that are derived from epithelial tissues is a transition from an epithelial cell type to a migratory mesenchymal cell type that can spread to other parts of the body. This change in cell behaviour also occurs, apparently by a similar mechanism, during the development of some normal tissue types. Here we propose to use an animal model of this process, coupled with advanced molecular genetic and cell biological techniques, to investigate a newly discov ....A critical step in the progression of cancers that are derived from epithelial tissues is a transition from an epithelial cell type to a migratory mesenchymal cell type that can spread to other parts of the body. This change in cell behaviour also occurs, apparently by a similar mechanism, during the development of some normal tissue types. Here we propose to use an animal model of this process, coupled with advanced molecular genetic and cell biological techniques, to investigate a newly discovered cell signalling mechanism required for the transition of cells from an epithelial form to a mesenchymal form. Understanding the molecular steps in this new pathway and discovering new genes involved will provide tools for understanding and preventing the metastasis of cancer cells.Read moreRead less
The Mechanism By Which Apical-basal Polarity Complexes Regulate The Salvador-Warts-Hippo Pathway
Funder
National Health and Medical Research Council
Funding Amount
$540,099.00
Summary
Cancer is a multi-hit process involving the activation of critical signaling pathways leading to increased proliferation, survival and increased invasion-metastasis. We have discovered that a neoplastic tumour suppressor gene, lgl, acts though the Salvador-Warts-Hippo (SWH) tumour suppressor pathway to inhibit cell proliferation and cell survival. Here we use the model organism, Drosophila, and mammalian epithelial cells to determine the mechanism by which Lgl activates the SWH pathway.
Investigating The Use Of Bone Marrow Transplantation To Study And Treat Polycystic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$349,250.00
Summary
Polycystic kidney disease (PKD) is a common genetic condition that causes fluid filled cysts to form in the kidney. In many cases, these cysts lead to kidney failure. Once the kidneys fail irreversibly, the only treatments available are dialysis and kidney transplantation. Dialysis to remove waste products from the blood is time consuming and does not completely replace all functions of the kidney. Kidney transplantation is limited by the availability of donor organs. At present, there are no re ....Polycystic kidney disease (PKD) is a common genetic condition that causes fluid filled cysts to form in the kidney. In many cases, these cysts lead to kidney failure. Once the kidneys fail irreversibly, the only treatments available are dialysis and kidney transplantation. Dialysis to remove waste products from the blood is time consuming and does not completely replace all functions of the kidney. Kidney transplantation is limited by the availability of donor organs. At present, there are no reliable ways to prevent the onset or slow the progression of PKD. The kidney consists of a complex system of tubules and ducts. PKD causes the cells that make up these tubules and ducts to grow uncontrollably and form cysts. We are using mice to study how mutations affect the mechanisms that control cell growth in the kidney and cause PKD. Bone marrow cells can move to the kidney and repair it after damage. We will test if bone marrow cells carrying a PKD mutation can cause PKD when transplanted into a healthy mouse. This will help us learn how mutations cause PKD in humans. We will also see if normal bone marrow can prevent disease when transplanted into a mutant mouse that spontaneously develops PKD. This experiment may lay the basis for a way to treat human PKD.Read moreRead less