Differential Cooperation Of MAPKs With TGF-beta Signaling In Epithelial-Mesenchymal Transition
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
Tumor metastasis - the spread of tumor cells from the original site of growth to other sites in the body, is the biggest threat to survival for patients with solid tumors. The most damage change during cancer progression is the switch from a locally growing tumor to a metastastic killer. For biologist studying cancer, a major challenge is to identify the molecular and cellular mechanisms underlying the switch of non-invasive tumor to an invasive, metastatic state. This application aims to identi ....Tumor metastasis - the spread of tumor cells from the original site of growth to other sites in the body, is the biggest threat to survival for patients with solid tumors. The most damage change during cancer progression is the switch from a locally growing tumor to a metastastic killer. For biologist studying cancer, a major challenge is to identify the molecular and cellular mechanisms underlying the switch of non-invasive tumor to an invasive, metastatic state. This application aims to identify key molecular and cellular mechanism controlling this switch, with the ultimate aim being to devise treatments that inhibit tumor metastasis. The results from this work will provide clear and specific targets to prevent and to treat tumor metastasis. More importantly, the success of strategies used in this work can potentially be used clinically for tumor treatment.Read moreRead less
Breast cancer is a common disease that is generally incurable if detected after it has spread to other organs. There is a lack of understanding of molecular events that drive the process. Cancers contain several types of host cells that contribute to the growth of the tumour, which can be regarded as wounds that never heal. Host cells are co-opted to promote continued growth of the cancer cells. It is the aim of this project to understand how these host cells promote the spread of breast cancer
Role Of PAK1 In Colorectal Cancer Growth And Metastasis Regulated By Gastrins
Funder
National Health and Medical Research Council
Funding Amount
$460,070.00
Summary
Increased level of PAK1(a protein kinase) was associated with the progression of colorectal (large bowel) cancer (CRC). Gastrin peptides are growth factors responsible for CRC development. The objective of this project is to determine the role of PAK1 in the regulation of CRC growth and metastasis by gastrin peptides. We will use cell culture, animal models and clinical samples in the program. A successful outcome will lead to the development of new CRC therapies such as inhibitors of PAK1.
Expansion Of TGF-beta-Smad Signaling Network And Intrinsic Epithelial-mesenchymal-endothelial Transition
Funder
National Health and Medical Research Council
Funding Amount
$557,297.00
Summary
The majority of tumor death occurs due to tumor metastasis. Both tumor growth and tumor spread require angiogenesis, which is thought to be driven by tumor but originated from host endothelial cells. Could tumor cells behave and function like endothelial cells? This application aims to detect the transition of adult epithelial cells to endothelial cells through a transient mesenchymal state. Our studies should reveal both the molecular and cellular causes of vasculogenic mimicry, thus establishi ....The majority of tumor death occurs due to tumor metastasis. Both tumor growth and tumor spread require angiogenesis, which is thought to be driven by tumor but originated from host endothelial cells. Could tumor cells behave and function like endothelial cells? This application aims to detect the transition of adult epithelial cells to endothelial cells through a transient mesenchymal state. Our studies should reveal both the molecular and cellular causes of vasculogenic mimicry, thus establishing a new paradigm in understanding tumor growth and metastasis. Such novel molecular understanding will open up new anti-tumor therapeutic opportunities.Read moreRead less
Recycling Of E-cadherin: Implications For Dynamic Cell Adhesion
Funder
National Health and Medical Research Council
Funding Amount
$250,494.00
Summary
E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During embryonic development E-cadherin is essential for establishing the normal body pattern and the cellular architecture of many epithelial organs. Throughout life E-cadherin serves to maintain epithelial barriers, such as the lining of the digestive tract. E-cadherin has been clearly identified as a tumour suppressor molecule: loss of normal E-cadherin function leads to tumour metastasis and ....E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During embryonic development E-cadherin is essential for establishing the normal body pattern and the cellular architecture of many epithelial organs. Throughout life E-cadherin serves to maintain epithelial barriers, such as the lining of the digestive tract. E-cadherin has been clearly identified as a tumour suppressor molecule: loss of normal E-cadherin function leads to tumour metastasis and cancer invasion. It is therefore essential to understand the physiological function and regulation of E-cadherin in cells. E-cadherin is normally expressed on the surface of cells for adhesion to neighbouring cells. Recently, we found that cells can internalise and recycle this surface E-cadherin: even in mature epithelia, a proportion of the E-cadherin molecules appear to undergo constant movement in and out of the cell. It is likely that this mechanism participates in the dynamic remodelling of adhesive contacts between cells in organs such as the gastrointestinal tract and during wound healing. Corruption of this recycling mechanism could also potentially contribute to tumorigenesis. In this grant we propose to build upon this discovery by investigating molecular and cellular mechanisms that mediate E-cadherin recycling. We will characterize the cellular pathways by which E-cadherin is trafficked. The signaling pathways that regulate recycling will be analysed, since these may be perturbed in cancer and inflammation. Other molecules that interact with E-cadherin will be studied to determine whether they too recycle. The information from these studies will have broad implications for understanding the role of E-cadherin in healthy organs and in common cancers.Read moreRead less
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
LIM KINASE 1 (LIMK1) AND METASTASIS, THE SEARCH FOR LIMK1 INHIBITORS
Funder
National Health and Medical Research Council
Funding Amount
$461,250.00
Summary
Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. Importantly, we have demonstrated that (1) inhibiting LIMK1 blocks the formation of metastatic ....Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. Importantly, we have demonstrated that (1) inhibiting LIMK1 blocks the formation of metastatic tumours in mice, and (2) introduction of this protein into tumour cells makes them more invasive. In addition, we find that the level of LIMK1 is much higher in human tumour cell lines that have the propensity to easily form tumours in mice. Also, measuring the level of this protein in cancer cells that spread to other organs shows that it is at significantly elevated levels when compared to normal tissue. The goals of this research are to: (1) understand whether the ability of LIMK1 to regulate tumour spreading and invasiveness correlates with its ability to control metastasis; (2) examine in human tumour samples whether the levels of LIMK1 correlate with the development of metastatic tumours; and (3) search for drugs that can inhibit the activity of this protein. The results from this research will be highly significant because LIMK1 levels are likely to be an important marker for which tumours will become metastatic. It is possible that, at the time of tumour diagnosis, LIMK1 measurements will enable the clinician to predict whether an individual tumour will become metastatic. Secondly, this protein is a novel drug development target. Drugs that inhibit this protein may block the ability of tumours to invade and metastasise.Read moreRead less