TMIC-79. LIPOCALIN-2 MEDIATES CELL-INTRINSIC FUNCTIONS IN GLIOBLASTOMA

Abstract

Abstract Glioblastoma (GBM) is the most common primary brain tumor with a median survival of 17-20 months. Despite therapeutic treatments including surgery, radiation, chemotherapy, a population of GBM cells, termed cancer stem cells (CSCs) are radio-resistant and chemo-resistant, leading to mortality of the patient. CSCs also have altered metabolic profiles and have an enhanced capacity to scavenge nutrients from their microenvironment, including iron. Lipocalin-2 (LCN2) functions to sequester iron and is traditionally considered an inflammatory marker through its function of limiting iron for bacterial usage; it has also been described to have both a pro and anti-tumorigenic and has context-dependent functions depending on iron status. LCN2 has been shown to be important in brain metastasis, but its role in GBM is still largely unknown. To assess a cell-intrinsic function for LNC2, we added recombinant LCN2 to low LCN2-secreting mouse GBM cell models and observed that proliferation also increased. When we knocked down LCN2 in our higher LCN2 secreting cell lines, we observed that knockdown cells had decreased viability and growth, which was not mediated by apoptosis, but rather, ferroptosis. When these cells were subsequently engrafted into wild-type mice, we observed an increase in survival. This effect was also phenocopied when the cells were implanted into LCN2 knockout mice, suggesting the tumor-intrinsic effect overpowered the global knockout model. Lastly, to investigate how LCN2 plays a role in the GBM microenvironment, we orthotopically implanted syngeneic mouse GBM cells into male and female LCN2 knockout and wild-type mice. We observed no survival difference, further suggesting that LCN2 does not function in an extrinsic manner. Taken together, these data suggest that LCN2 affects proliferation and tumorigenesis, and is another avenue to understanding the complexity of GBM biology. Strategies to reduce LCN2 in GBM may provide a therapeutic target for GBM in the future.