Role of autophagy in chemioresistance of glioblastoma stem-like cells

Malignant gliomas are the most frequent primary brain tumors, with the median survival rate of patients being about one year. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. Gliomas contain a rare subpopulation of cells with stem cell-like properties, so-called glioblastoma stem cells (GSC). These cells are believed to be responsible for tumor initiation, recurrence and failure of conventional therapies. Cancer stem cells are defined as undifferentiated cells with self-renewal ability and can differentiate into multiple lineages. Once forced to differentiate, these cells lose their properties and become more sensitive to chemotherapy. Molecular mechanisms determining differentiation and chemo-sensitivity of GSCs remain poorly defined.   

The autophagy is a catabolic process that involves the degradation of unnecessary or dysfunctional cellular components through the cell lysosomal machinery. Autophagy serves to maintain cell homeostasis but is activated in response to cellular stress under pathological conditions. Recent data clearly demonstrate that autophagy is a double-edged sword that could be either protective or detrimental to cells, depending on the nature of the stimulus and extent of autophagy-induction. Additionally, the capacity of autophagy to recycle cellular components and provide energy could support the differentiation process.

The purpose of this project is to investigate the role of autophagy in GSC resistance to chemotherapy and to modulate these processes. We hypothesised that the induction of autophagy, which may regulate the differentiation of cells, sensitises GSCs to anti-cancer drugs. To determine the potential role of autophagy in differentiation and regulation of cancer stem cells response to drugs, we will use chemical or genetic autophagy inhibitors. Cancer stem cells will be isolated from glioma cell lines and from glioma surgical samples. Our results will uncover the basic mechanisms of glioma biology and shed light on the relationship between autophagy and cell differentiation, but, more importantly, it will reveal mechanisms of glioma cancer stem cell resistance to chemotherapy. Our studies may discover novel biological targets that will contribute to designing innovative therapeutic strategies, aimed at the selective elimination of glioma stem cells or induction of their differentiation.

Dr. Iwona Ciechomska

Obtained a PhD degree at the Nencki Institute of Experimental Biology, Warsaw, Poland under the supervision of Professor Bozena Kaminska. Her PhD project was focused on the role of Akt kinase and its downstream target, Forkhead transcription factor in transcriptional regulation of ligand Fas expression during apoptosis of glioma cells. She did postdoctoral training in Dr Aviva Tolkovsky’s lab at the Department of Biochemistry, University of Cambridge, where she investigated the relationship between apoptosis and autophagy; specialising in whether the interaction of Beclin 1 with Bcl-2 alters the ability of Bcl-2 to protect cells from apoptosis. Her current project focuses on understanding the molecular mechanisms responsible for chemoresistance of glioblastoma stem-like cells and their role in glioma pathogenesis.

Date of publication: 30^th Jul, 2012