Podxl as therapeutic target for metastasis
Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients.
Recently, we found that high podocalyxin (gene name PODXL, protein name Podxl) expression is associated with high metastatic profile in OS cell lines. Consistent with this data, we found a significant association between high Podxl expression and poor outcome in pediatric osteosarcoma patients. Podxl is a cell surface transmembrane glycoprotein, belonging to the CD34 family. The functional role of Podxl in tumorigenesis is largely unknown, but it has been demonstrated to promote cancer cell invasion and migration and to enhance metastatic potential. Podxl is upregulated on a variety of human tumors, facilitates disease progression and is a promising target for immunotherapy as an approach to blocking metastatic disease.
Accordingly, in collaboration for the Centre for Drug Research and Development, Kelly McNagny and his collaborators have developed a novel panel of monoclonal antibodies to human Podxl and have explored their utility in suppressing tumor cell growth in vitro and in vivo.
To define the relevance of Podxl in the biology of metastasis, we examined Podxl expression in different OS cells lines with different metastatic profiles. Then, we studied the importance of Podxl in migration and invasion processes and in in vitro3D cell system formation. To assess Podxl’s role in the metastatic progression we performed the pulmonary metastasis assay (PuMA). PuMA is an ex vivolung explant and closed cell culture system that permits to study the biology of lung colonization by fluorescence microscopy. With PuMA model, we assessed the effects of anti-metastatic therapeutics over time.
In the present study, we found that the suppression of Podxl in OS profoundly impairs cell proliferation, migration, and invasion properties and tumorspheres formation in OS cells in vitro. With PuMA model, we found that Podxl is required for the progression of metastasis disease. These data tend to validate podocalyxin as a regulator of tumor progression and a novel therapeutic target in OS.
It is necessary to perform in vivo experiments to further explore the functions of Podxl and the effect of the podocalyxin-specific monoclonal antibody (coupled or not to a toxic payload) to suppress the metastasis progression in our model.