P3.44. LACK OF SORLA UNLOCKS THE PRO-INFLAMMATORY POTENTIAL OF GLIOMA-ASSOCIATED MICROGLIA
Paulina Kamińska1,2, Salwador Cyranowski3, Magda Bakun4, Ewa Sitkiewicz4, Paulina Pilanc-Kudlek2, Bożena Kamińska2, Anna R. Malik1
1 Cellular Neurobiology Research Group, Faculty of Biology, University of Warsaw, Poland
2 Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
3 Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland
4 Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Warsaw, Poland
INTRODUCTION: SorLA (SORL1 gene) is a sorting receptor which transports its protein cargoes between subcellular compartments and therefore defines their final localization. While SorLA was initially thought to be limited to neurons in the brain, it was later discovered to be expressed in glial cells as well, including microglia, which depending on the pathological context may acquire various functional properties. For instance, during glioblastoma (GBM) progression, both brain-resident microglia and blood-derived macrophages are reprogrammed, and instead of fighting the tumor, promote its growth through secretion of pro-tumorigenic factors. These cells are collectively called glioma associated microglia and macrophages (GAMs). Finding a mechanism responsible for the phenotypic polarization of GAMs is crucial for the development of new therapeutic strategies in the GBM treatment. Interestingly, our previous studies indicated that expression of SORL1 in human and mouse GAMs is upregulated [Kaminska et al., 2024].
AIM(S): To characterize the role of SorLA in shaping properties of GAMs.
METHOD(S): Primary mouse microglia were used in in vitro experiments. The impact of SorLA on glioma microenvironment was assessed in mouse GL261 gliomas implanted to wild-type (WT) and SorLA-deficient (SorLA-KO) mice.
RESULTS: We observed that the level of Sorl1 transcript depends on the activation mode of microglia. Also, lack of SorLA unlocks the ability of microglia to release higher amounts of pro-inflammatory factors when compared to WT cells. Furthermore, SorLA-KO microglia co-cultured with GL261 cells seem to exhibit enhanced phagocytosis and interferon-related responses. Our in vivo studies revealed that SorLA-KO mice develop smaller gliomas than the WT group, which coincides with pro-inflammatory activation of microglia and changes in the infiltration of immune cells from the periphery.
CONCLUSIONS: SorLA is a key player in shaping properties of microglia and its depletion unlocks their anti-tumor response, which prevents glioma growth.
FINANCIAL SUPPORT: Studies were supported by the National Science Center, Poland (2020/37/B/NZ3/00761, AM; 2023/49/N/NZ4/01690, PK) Foundation for Polish Science co–financed by the EU under the European Regional Development Fund (POIR.04.04.00 00 5CEF/18 00, AM) and I.3.4 Action of the Excellence Initiative - Research University Programme at the University of Warsaw.