The Role Of TGF-beta Signaling In Suppression Of Stat3-mediated Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$667,000.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach mining cells. Our proposal combines the expertise of the two investigators in signal ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach mining cells. Our proposal combines the expertise of the two investigators in signal transduction and the making of genetically modified mouse models. These strategies will be employed to specifically address in the laboratory mouse the function of two specififc signaling cascades, called Stat3 and TGF-beta. The identification of detailed description by which these molecules causally relate to cancer formation will provide clear and specific molecular targets for future therapies to treat various cancers, including those of the stomach.Read moreRead less
Regulator Of G-protein Signalling-5: A Key Modulator Of Vascular Maturation And The
Funder
National Health and Medical Research Council
Funding Amount
$548,396.00
Summary
Tumours progressively grow in part because they escape destruction by the immune system. New blood vessels grow inside tumours by a process called angiogenesis, which in turn stops disease-fighting cells in their tracks. However, we have now discovered that it is possible to reverse angiogenesis by normalising the blood vessels. This effectively means the barriers are broken down and the tumour can be opened to the immune system or cancer fighting drugs. Furthermore, we have identified a protein ....Tumours progressively grow in part because they escape destruction by the immune system. New blood vessels grow inside tumours by a process called angiogenesis, which in turn stops disease-fighting cells in their tracks. However, we have now discovered that it is possible to reverse angiogenesis by normalising the blood vessels. This effectively means the barriers are broken down and the tumour can be opened to the immune system or cancer fighting drugs. Furthermore, we have identified a protein which appears to be very important for normalisation, a process which is currently not well understood. This proposal continues our pioneering work on vessel normalisation and will use models of highest clinical relevance to study the dynamics of vessel remodelling in tumours. Our approach is different to current angiogenesis research which simply tries to block or destroy the blood vessels that feed tumours. We expect our findings to lead to highly specific and effective anti-tumour therapies. Moreover, vessel growth in tumours has striking parallels to other vascular processes in the body, which have important implications for major and common human diseases such as high blood pressure and atherosclerosis. We now have the tools to study these processes and their abnormalities in our newly established disease model. By gaining insight into these disorders we will be able to develop novel approaches to stop disease progression.Read moreRead less
Functional Analysis Of The Molecular Switch That Regulates ADAM10-mediated Cleavage Of RTK Ligands In Tumour Cells.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of th ....We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of the ephrin by ADAM10 which also functions in other cancer promoting events by cleaving growth factors. Our structure reveals how Eph-bound ephrin is specifically targeted by ADAM. We will now determine the relevance of this mechanism for other ADAM10 targets, and design drugs to bind this region and inhibit ADAM function, which we will test in assays measuring tumour cell movement and growth, with the aim of developing therapies to block cancer progression.Read moreRead less
The Role Of MIC-1 In The Promotion And Progression Of Skin Squamous Cell Carcinoma.
Funder
National Health and Medical Research Council
Funding Amount
$237,258.00
Summary
Skin cancers are the most common human tumours and the incidence is increasing. Ultra-violet (UV) light is the main factor in the formation of skin cancer. This project will find how a gene product (MIC-1) induced by solar UV affects the skin, and why we see it in skin cancers. This protein has other interesting properties that could bear directly on measuring sun exposure and understanding skin cancer. A processed form is released into the blood, where it could carry UV signals and be used in p ....Skin cancers are the most common human tumours and the incidence is increasing. Ultra-violet (UV) light is the main factor in the formation of skin cancer. This project will find how a gene product (MIC-1) induced by solar UV affects the skin, and why we see it in skin cancers. This protein has other interesting properties that could bear directly on measuring sun exposure and understanding skin cancer. A processed form is released into the blood, where it could carry UV signals and be used in population studies as a measure of sun exposure. It's also induced by certain cancer-promoting chemicals which resemble UV light in their immediate effects. A lot could therefore be learnt from this protein, and if we find that MIC-1 promotes the growth of normal and tumour cells in the skin after UV exposure, we can look for ways to stop this happening.Read moreRead less
MECHANISMS OF MOTILITY AND METASTASIS In BREAST CANCER
Funder
National Health and Medical Research Council
Funding Amount
$209,505.00
Summary
The broad aim of this proposal is to elucidate novel molecular mechanisms of breast cancer cell motility that are relevant to metastasis or the spread of cancer. The function of two genes will be studied. We propose that (1) reduced on-random motile (ROM) regulates the speed of cancer cell movement, and (2) Neural Wiskott-Aldrich syndrome protein (N-WASP) regulates the directional component of cell movement. We will relate the function of ROM and N-WASP to rapid, linear walking along collagen fi ....The broad aim of this proposal is to elucidate novel molecular mechanisms of breast cancer cell motility that are relevant to metastasis or the spread of cancer. The function of two genes will be studied. We propose that (1) reduced on-random motile (ROM) regulates the speed of cancer cell movement, and (2) Neural Wiskott-Aldrich syndrome protein (N-WASP) regulates the directional component of cell movement. We will relate the function of ROM and N-WASP to rapid, linear walking along collagen fibres in live tumours and to breast cancer metastasis to the lung. ROM will be inhibited in breast cancer cells and we expect increases in both the speed of cell movement and metastasis. Therefore, ROM functions as a suppressor of metastasis. Inhibition of N-WASP, however, is expected to compromise both the directionality of cell movement and metastasis. N-WASP is therefore, a promoter of metastasis. At the completion of this work, the regulatory mechanisms of motility and metastasis by ROM and N-WASP will be defined. This will facilitate the development of biologically targeted agents for ROM and N-WASP that can be used to control metastasis. In addition, these agents that target the motility pathway are appropriate for use in combined therapy with agents that target a different pathway such as survival or growth. This will significantly improve disease control rates or the proportion of patients with partial or complete disease regression. This proposal addresses the National Health Priority, cancer, and related National Research Priority, ageing well and ageing productively, where in the longer term, we will be able to create new and much needed therapy for metastasis.Read moreRead less