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CURRENT RESEARCH PROJECTS

Project

The control of sarcoma cell metastasis through the novel AFAP1L1 pathway.

Project

The control of sarcoma cell metastasis through the novel AFAP1L1 pathway.

Project Outline

Research area
Cell Signaling

Laboratory
Cancer and Cell Biology

Project

The control of red blood cell longevity and integrity through Lyn/Src Family Kinase pathways.

Project

The control of red blood cell longevity and integrity through Lyn/Src Family Kinase pathways.

Project Outline

Research area
Cell Signaling

Laboratory
Cancer and Cell Biology

Project

Identifying new therapy options for sarcoma patients through personalized genomic medicine.

Project

Identifying new therapy options for sarcoma patients through personalized genomic medicine.

Project Outline

Research area
Cell Signaling

Laboratory
Cancer and Cell Biology

Project

Studying the magnitude of the effect of enzyme variations on the ability of young cancer patients to handle High-Dose-Methotrexate (HDMTX) treatment, as HDMTX can causes severe toxicities.

Project

Studying the magnitude of the effect of enzyme variations on the ability of young cancer patients to handle High-Dose-Methotrexate (HDMTX) treatment, as HDMTX can causes severe toxicities.

Project Outline

Research area
Cell Signaling

Laboratory
Cancer and Cell Biology

Project

Using personalized genomic medicine to identify potential new therapeutic potions for sarcoma patients.

Project

Using personalized genomic medicine to identify potential new therapeutic potions for sarcoma patients.

Project Outline

Research area
Cell Signaling

Laboratory
Cancer and Cell Biology

CURRENT STUDENT PROJECTS

Student Project

Signalling networks in the regulation of red blood cell integrity and survival

Student Project

Signalling networks in the regulation of red blood cell integrity and survival

Project Outline

Red blood cells (RBCs, erythrocytes) are essential for transport and exchange of O22/CO22 around the body. To relieve anaemia caused by trauma, surgery, chemotherapy, radiotherapy, bone marrow failure, cancer/leukaemia induced anaemia, RBC transfusion (a >$20billion industry) using stored blood (stored for up to 42 days at 4°C) is essential. Stored blood becomes compromised over time resulting in the RBC “storage lesion” that can significantly impact on RBC function and lifespan following transfusion (25% of transfused RBC are lost within 24h of transfusion). This can lead to failure to alleviate the symptoms of anaemia and untoward clinical effects from iron and proinflammatory mediators released by compromised RBCs. The health system costs and clinical complications from the RBC storage lesion place a considerable global health and economic burden on society. The precise mechanisms for this are poorly understood. Our laboratory was the first to establish the importance of the signalling molecule Lyn (a Src family tyrosine kinase, SFK) in erythroid cells and mature RBCs, and we postulate that abnormalities in Lyn may occur during red cell storage. Lyn is a key kinase that phosphorylates the major RBC membrane-cytoskeleton anchor Band3 that regulates metabolism, membrane transport and shape, which are essential for RBC integrity.
Hypotheses
(i) Signalling pathways involving Lyn play critical kinase-dependent and independent roles in RBCs, regulating integrity, response to stress (physical, osmotic, oxidative), longevity and survival.
(ii) Targeting and perturbing Lyn/SFK signalling pathways will have clinical applications for RBC abnormalities and disorders, as well as RBC storage and transfusion.

Aims
• Fully characterise the contribution of signalling networks involving Lyn/SFKs to RBC longevity, deformability, responses to stress (in vitro and in vivo), during RBC storage and transfusion in mice, as well as its importance for human RBCs (in vitro) in regard to the RBC storage lesion.
• Delineate central RBC biochemical/signalling networks and cellular biological consequences of manipulation of Lyn levels and kinase activity.
• Assess the capacity of agents targeting Lyn and SFKs as potential therapies for ameliorating RBC pathologies associated with altered Lyn/SFK levels and/or activity.

Contact
Associate Professor Evan Ingley – [email protected]

Chief supervisor
Associate Professor Evan Ingley

Project suitable for
PhD

Essential qualifications
BSc Hons

Student Project

Control of bone cancer cell migration and invasion by the scaffold protein

Student Project

Control of bone cancer cell migration and invasion by the scaffold protein

Project Outline

Osteosarcoma (OS) is the most prevalent primary bone tumour. It is prominent in adolescents and young adults, being the 5th leading cause of cancer death in this age group. OS also has an incidence peak in people over 50 years of age. The current optimal therapy for OS involves high dose cytotoxic drugs and surgical resection. This has led to improved prognosis over the last 40 years with sustained overall survival rates approaching 70% for patients with localised (non-metastatic) cancer at diagnosis. However, up to 20% of patients present with metastatic disease and the majority of recurrences after therapy for local disease are also metastatic. We identified a new and important regulator of OS cell migration and invasion AFAP1L1 (Actin Filament Associating Protein-1-Like-1) that shows strong association with metastatic disease. We detailed the molecular pathway that AFAP1L1 mediates at the cellular level3 to promote OS cell migration and invasion, critical aspects of metastatic disease, through specialized subcellular protrusions called invadopodia. These are actin-rich structures facilitate delivery of metalloproteases to mediate extracellular matrix (ECM) degradation, thereby promoting cancer cell migration and invasion, processes intrinsic to metastatic spread. AFAP1L1 is a scaffold protein that both provides direct links between the multiple critical pathways that govern invadopodia function, and receives inputs from growth factors and integrins, to regulate cytoskeletal components of the invadopodia.
Hypotheses
1. AFAP1L1 plays a critical, direct role in OS metastasis by acting as a scaffold facilitating invadopodia-driven cell migration, invasion and dissemination.
2. AFAP1L1 expression and/or phosphorylation status is a marker of OS metastasis and can potentially be used as a diagnostic indicator of malignant OS development.
3. Inhibition of AFAP1L1 expression in OS cells and in animal models of OS will reduce metastatic disease, thus cement AFAP1L1 as an important potential therapeutic target
4. Critical regions of AFAP1L1 can be used as dominant negative moieties to reduce the metastatic potential of OS cells and thus uncover potential avenues to guide the development of targeted therapies for metastatic OS.

Aims
1. To knockout AFAP1L1 gene expression in cell and animal models of OS and ascertain its importance for tumour development and metastasis through controlling cell migration and invasion in vitro and in vivo.
2. To correlate the expression level and activity status of AFAP1L1 (phosphorylation) with OS development and metastasis; providing strong evidence for its potential as a diagnostic and/or predictive marker of disease development.
3. To identify minimal critical regions of AFAP1L1 that regulate OS migration, invasion and metastasis in vitro and in vivo, and can act as dominant negative/positive moieties, potentially identifying targetable motifs for the purpose of therapeutic development.

Contact
Associate Professor Evan Ingley – [email protected]

Chief supervisor
Associate Professor Evan Ingley

Project suitable for
PhD

Essential qualifications
BSc Hons