Cancer stem cells, plasticity and tumor heterogeneity in glioblastoma

Glioblastoma (GBM) is the most aggressive form of primary brain tumors. Standard of care for newly diagnosed GBM consists of maximal surgical resection followed by radiation and chemotherapy. Despite this treatment, recurrence is almost inevitable and the prognosis remains poor. Recurrent disease maybe a result of the enrichment of self-renewing glioma stem cells (GSCs). Our previous work suggested that GSCs can originate from de-differentiation of transformed mature astrocytes or neurons. This plasticity allows the tumor to sustain itself by creating a constant pool of differentiated and GSCs.

RNAseq analysis of differentially expressed genes in de-differentiated transformed astrocytes and neurons compared to their parental cells revealed Filamin A (FLNA) to be overexpressed.
FLNA is an actin binding protein, in charge of cytoskeleton organization and is a scaffold to cytoplasmic signaling proteins. FLNA is overexpressed in multiple types of cancer, including GBM, with high levels of the protein being associated with poor prognosis. However, the role FLNA in malignancies, particularly in GBM, is unclear. To assess the possible role of FLNA in glioma cell plasticity, we knockdown the expression of FLNA in glioma cells. Silencing FLNA in differentiated glioma cells resulted in morphological changes and we believe these changes might be related to alterations in the cytoskeleton of the cells. Silencing FLNA also compromised the plasticity of glioma cells and in vivo transplantation of FLNA-KD cells increased the survival of mice. We suggest FLNA induces and promotes cancer cell differentiation in GBM and contributes to the heterogeneity of the tumor.