TMIC-39. Investigating the role of PDGF-AA in invasive melanoma brain metastases

Approximately 20-40% of cancer patients develop brain metastases (BrM). Unfortunately, these patients suffer from poor outcomes, diminished quality of life and approximately 60% of patients that undergo BrM resection recur within 1 year. Our group described histological growth patterns associated with recurrence, where highly invasive (HI) BrM are more likely to recur locally, compared to minimally invasive (MI) BrM. Cancer cell invasiveness can be driven by crosstalk with the microenvironment, through secreted factors from brain cells or from cancer cells that colonize the brain. We have profiled the secretome of HI and MI patient-derived xenograft BrM using mouse- and human-specific multiplex ELISA. This screen revealed high levels of platelet-derived growth factor A (PDGF-AA) in HI melanoma BrM and these findings were confirmed in independent syngeneic melanoma brain tumour models. Importantly, overexpression of PDGF-AA in MI melanoma cells accelerated intracranial tumour growth and shortened survival in vivo. There are several studies reporting autocrine PDGFRα signaling downstream of PDGF-AA in aggressive glioblastomas. Therefore, we explored the initial hypothesis that PDGF-AA might activate cancer cell intrinsic PDGFRα signaling to promote invasion. However, we demonstrate that such an autocrine signaling mechanism is not operative in our models. Considering these results, we are now exploring the hypothesis that melanoma cell-derived PDGF-AA acts on parenchymal cells in the brain to promote BrM aggressiveness. Brain microenvironmental remodeling factors are important to investigate as potential druggable targets in BrM. Should PDGF-AA be involved, clinically available PDGFRα inhibitors could be a potential treatment option to disrupt such crosstalk in individuals with recurring BrM.