Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity

Abstract

Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma‐initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy‐resistant MES‐like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single‐cell level and strongly correlated with our previously defined therapy‐resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy‐resistant MES‐like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long‐term exposure to the proinflammatory cytokine interleukin 1 beta (IL1β). IL1β induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive‐astrocyte‐like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called ‘reactive GICs’. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor‐promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment‐resistant relapse‐driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Identification of a mesenchymal-related signature associated with clinical prognosis in glioma

“…MES is the most malignant glioblastoma and has a worse prognosis [ 24 ]. On the one hand, it has stronger resistance to treatment than other types of gliomas [ 25 ]. This therapeutic resistance may be related to the high expression of inflammation-related genes and NF-kB activation [ 8 ], which is consistent with our results.…”

“…Inflammation-related genes are also highly expressed in the MES subtype [ 8 , 33 – 35 ]. Epithelial-to-mesenchymal transition is a common pattern of increased malignant behavior and disease progression of epithelial tumors, and the MES phenotype is closely related to this change [ 25 ]. This finding supports our GSEA results.…”

LINC01116 promotes tumor proliferation and neutrophil recruitment via DDX5-mediated regulation of IL-1β in glioma cell

“…It has been reported that ectopic expression of CD133 in glioma cells could promote neutrophil recruitment by regulating IL-1β and its downstream chemokines 14 . In addition, IL-1β could significantly promote the self-renewal of glioma stem cells, and trigger the transition of glioma-initiating cells into a mesenchymal (MES) cell state 44,45 . In this study, we found that the expression of IL-1β steadily decreased after knockdown of LINC01116, thereby reducing neutrophil recruitment and glioma proliferation.…”

SNHG29 regulates miR-223-3p/CTNND1 axis to promote glioblastoma progression via Wnt/β-catenin signaling pathway

“…Glioblastoma is one of the most lethal types of tumors in the central nervous system [12]. Surgery section, chemotherapy and radiotherapy were widely adopted to treat patients with malignant brain tumor whereas the result of these methods did not improve patient’s condition [13]. The pathology and progression of glioblastoma was associated with both genetic and epigenetic changes [14].…”