TMIC-82. LIPOCALIN-2 MEDIATES CELL-INTRINSIC AND CELL-EXTRINSIC 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 subset of GBM clones, 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. LCN2 has 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 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. Female LCN2 knockout mice succumbed to tumors faster compared to males, revealing another example of sex differences in the tumor microenvironment. To assess a cell-intrinsic function for LNC2, we added recombinant LCN2 to mouse GBM cell lines and saw that proliferation also increased. When we probed for receptor expression in our knockdown cell lines, we saw that the LCN2 canonical receptor, SLC22a17, was upregulated in response. Furthermore, in a subset of slow-cycling cells of CSCs, LCN2 was shown to be up-regulated. Taken together, these data suggest that LCN2 functions in an iron-dependent manner to affect proliferation and sex-specific tumorigenesis. Given the fact that males have more iron than females, it is worth investigating the role of iron in GBM sex difference progression and therapeutic targets.