Every cell in our body has an intrinsic orientation that is controlled by a universal set of genes known as polarity genes. Loss of this orientation is a common and early feature of cancer. We have identified the gene Scribble as a gene that controls cell orientation and is essential to prevent the development of prostate cancer. We propose experiments to discover how Scribble controls prostate cancer and whether it can be used to better predict outcome for prostate cancer patients.
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
Characterization Of Novel Inhibitors Of G1-S Phase Progression In Drosophila
Funder
National Health and Medical Research Council
Funding Amount
$456,000.00
Summary
Cancer is a disease that affects 1-3 people and therefore, understanding the mechanisms by which cancer arises 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. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell p ....Cancer is a disease that affects 1-3 people and therefore, understanding the mechanisms by which cancer arises 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. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, the vinegar fly, Drosophila. A key regulator of cell proliferation in all multicellular organisms is Cyclin E, which is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer-causing mutations result in up-regulation of this critical cell cycle regulator. We have used a genetic approach to identify novel negative regulators of Cyclin E. This proposal seeks to further clarify the mechanism by which the identified Cyclin E interactors regulate cell cycle progression. In addition, this proposal seeks to identify the genes encoding other cyclin E interactors, expected to be novel tumor suppressors. The expected outcome of this project is to elucidate novel genes and mechanisms that control cell proliferation 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
Dissecting PTEN-regulated Pathways In The Genesis Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$302,981.00
Summary
Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The PTEN phosphatase is one of the most common targets for inactivation in melanoma. The precise role of PTEN and its contribution to melanoma development have not been thoroughly explored. This work will highlight potentially novel pathways and molecules that are likely to be critical in the genesis of melanoma and to the ratio ....Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The PTEN phosphatase is one of the most common targets for inactivation in melanoma. The precise role of PTEN and its contribution to melanoma development have not been thoroughly explored. This work will highlight potentially novel pathways and molecules that are likely to be critical in the genesis of melanoma and to the rational approach to targeted therapy.Read moreRead less
Using Mouse Models To Decipher The Function Of Caspase-2 In Limiting Aneuploidy Tolerance And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$871,162.00
Summary
Aneuploidy or abnormal chromosome number is a feature of cancer cells. The extent of aneuploidy is often predictive of prognosis and the effectiveness of cancer treatment. We discovered that a tumour suppressing protein, caspase-2, is important for deleting aneuploid cells that may otherwise become cancerous. In this project we will use cancer models to decipher how caspase-2 safeguards against aneuploidy and cancer to better understand how cancer cells can survive and be targeted for treatment.
Examination Of The Mechanism By Which The Salvador/warts/hippo Complex Restricts Cell Growth And Number
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created r ....Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created random mutations in the vinegar fly, Drosophila, and tested their ability to cause solid cancers. Drosophila is an excellent model organism for this study because many of the pathways that are often perturbed in cancer are conserved between humans and flies. Using this approach we identified several known and novel genes that cause cancerous growths. By studying the human counterparts of these novel genes we identified a potential role for some of these genes in the generation of human cancer. Three of these genes, hippo, salvador and warts, appear to act in concert to restrict cell number. In this study we aim to understand the mechanism by which these genes restrict cell number. To do this we will analyze how the activity of this pathway is controlled and in what tissues it functions. We also plan to discover other key components of this pathway that function downstream of hippo, salvador and warts. To perform these experiments we will use a variety in vitro biochemical techniques as well as experiments in tissue culture cells. We will then verify the results of these experiments in the context of a whole animal. By performing these experiments we hope to gain greater insight into the genesis of cancer.Read moreRead less
Elucidating The Cellular Processes That Are Critical For P53 Mediated Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$1,016,108.00
Summary
p53 is a tumour suppressor gene that is mutated in ~50% of human cancers. Mutations in p53 cause development of cancer and render malignant cells resistant to chemotherapy. We have identified genes regulated by p53 that appear critical for its tumour suppressive function. In this project, we will use innovative novel genetic tools to discover the cellular and biochemical functions of these genes. The ultimate goal of our studies is to identify novel targets for anti-cancer therapy.
The Role Of Necroptosis In Development, The Immune System And Autoimmune Pathology
Funder
National Health and Medical Research Council
Funding Amount
$454,105.00
Summary
Programmed cell death plays critical roles in development and cell-turnover in the adult. Defects in this process can cause cancer or autoimmune diseases. We will use genetic and biochemical approaches to define the individual roles of necroptosis, a newly described cell death process, and those overlapping with apoptosis in normal development and cell-turnover as well as in cancer and autoimmune diseases. The objective of this work is to identify potential targets for therapeutic intervention i ....Programmed cell death plays critical roles in development and cell-turnover in the adult. Defects in this process can cause cancer or autoimmune diseases. We will use genetic and biochemical approaches to define the individual roles of necroptosis, a newly described cell death process, and those overlapping with apoptosis in normal development and cell-turnover as well as in cancer and autoimmune diseases. The objective of this work is to identify potential targets for therapeutic intervention in cancer or immunopathology.Read moreRead less
A Novel Role For Proteolysis In Promoting Inner Ear Cell Injury And Hearing Loss
Funder
National Health and Medical Research Council
Funding Amount
$972,818.00
Summary
Nearly 40% of hearing loss is attributable to traumatic noise exposure. This project will test a new idea that cells in the inner ear are damaged and die via noise-induced proteolysis, and investigate whether a similar mechanism operates during age-related hearing loss. It will open new avenues for therapies to preserve hearing where trauma is unavoidable, or has occurred through accident or incident.
Deciphering The Function Of Caspase-2 In DNA Damage Response And Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$808,007.00
Summary
Aberrant cell death and DNA damage response (DDR) are hallmarks of tumourigenesis. Recently we have discovered that an enzyme, caspase-2, previously implicated in cell death execution, also works in DDR and acts as a tumour suppressor. We now wish to validate these finding in preclinical models of cancer and understand precisely how caspase-2 safeguards against cancer development. These studies will help better understand tumourigenesis and may lead to the discovery of new drug targets.