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.
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.
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.
Associate Professor Evan Ingley – [email protected]