Control of Bone Cancer Cell Migration and Invasion by the Scaffold Protein AFAP1L1

Honours / Masters Project 2017

Control of bone cancer cell migration and invasion by the scaffold protein AFAP1L1.

Interested students should contact Andrew Currie the Honours Chair for Biomedical Science Honours to discuss supervision arrangements with Murdoch University.

Short project description & main objectives:
Osteosarcoma (OS) is the most prevalent primary bone tumour. It is prominent in adolescents and young adults. 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.Recently 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.
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 preliminary analsysisin 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 moieties, potentially identifying targetable motifs for the purpose of therapeutic development.
Principal supervisor: / A/Prof. Evan Ingley
Other supervisors: / A/Prof. Fiona Pixley, Prof. David Wood
Contact details for furtherinformation: / A/Prof. Evan Ingley ()
Closing date for applications: / 20 Feb 2017
Start & finish date of project: / 20 Feb 2017- November 2017
Available part-time? / Yes
Available to international students? / Yes
Research centre/group: / Cell Signalling Group, Harry Perkins Institute of Medical Research
Desired background of applicants: / Biochemistry, cell biology, molecular biology, mouse biology.
Additional funding/scholarship provided: / Project funded through Cancer Council of WA
Other benefits: / The chance to undertake state of the art research at a leading research institute with world-class facilities and a strong collegial culture.

School of VLS23 January 2017