CELL SIGNALING

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.

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.