Rola receptora sortującego SorLA w polaryzacji fenotypu mikrogleju w glejaku : praca doktorska

Kamińska, Paulina

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Rola receptora sortującego SorLA w polaryzacji fenotypu mikrogleju w glejaku : praca doktorska

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Title: Rola receptora sortującego SorLA w polaryzacji fenotypu mikrogleju w glejaku : praca doktorska

Abstract:

Glioblastoma (GBM) is the most common and most aggressive brain malignancy in adults, with a median patients’ survival of only 14 months. A hallmark feature of GBM is its complex microenvironment, largely composed of microglia and macrophages: immune cells which in theory should fight with the tumor. However, factors secreted by glioma cells drive the phenotypic polarization of microglia and macrophages, so instead of limiting tumor development, they support its growth and suppress anti-tumorigenic response. As a result, these cells constitute key mediators of the immunosuppressive nature of the GBM microenvironment. Such re-programmed microglia and macrophages are collectively called glioma-associated microglia and macrophages (GAMs) and may account for up to 30% of the tumor mass. Therefore, finding molecular mechanisms responsible for shaping tumor- supportive properties of GAMs is crucial for the development of new therapeutic strategies of GBM. SorLA protein (encoded by SORL1 gene) is an intracellular sorting receptor which transports its protein cargoes between different subcellular organelles and therefore defines their final localization. While the presence of 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. Interestingly, according to publicly available data from analysis of human GBM samples transcriptomes, SorLA seems to be important in shaping functional properties of GAMs. In line with this notion, the overall aim of this study was to decipher the influence of SorLA on the properties of GAMs, in particular microglia. Experiments performed in the frame of the PhD dissertation revealed that the level of Sorl1 transcript in primary mouse microglia depends on the activation mode of the cells. Furthermore, it turned out that lack of SorLA unlocks the ability of microglia to release pro- inflammatory factors, including TNF-α, when compared to wild type cells (WT). Microglia depleted of SorLA (SorLA-KO) upon co-culture with mouse glioma cells are characterized by increased level of proteins linked to interferons-related response and phagocytosis, which indicates their pro-inflammatory activation. These findings raised the hypothesis that the lack of SorLA may unlock the pro-inflammatory potential of microglia and thereby could influence the properties of glioma microenvironment. Indeed, using mouse model of glioma it was observed that SorLA-KO mice develop smaller brain tumors when compared to WT animals, which coincides with changes in microglia morphology suggesting their inflammatory activation. Simultaneously, GAMs from SorLA-KO microenvironment are characterized by increased expression of genes linked to interferons-related response, while the levels of transcripts linked to tumor-supportive functions of the cells are decreased. Finally, in glioma microenvironment of SorLA-KO mice, increased levels of markers related to necroptotic type of cell death are observed, as well as changes in the profile of infiltrating immune cells.
In summary, presented research indicates that SorLA is a key player in shaping the properties of GAMs and its depletion unlocks their anti-tumor response which influences the overall potential of glioma microenvironment and as a result, prevents tumor growth.