Dedifferentiation of human Glioma cells by reprogramming confers cancer stem cell properties

Abstract

Cancer stem cells (CSCs) are dedifferentiated malignant cell populations able to initiate and maintain tumour heterogeneity and believed to be able to evade therapy. CSCs have thus emerged as responsible for metastasis and secondary tumour formation, making them an attractive and obligatory therapeutic target. There are two prevailing theories attempting to explain the appearance of stem cells with malignant properties: a) that transforming mutations occur in pre-existent adult stem cell populations already bearing self-renewal and multilineage differentiation properties; b) that cancer progression contributes to the dedifferentiation of transformed somatic cells and their transition towards a stem cell phenotype. Previous work of Dr. Sancho-Martinez demonstrated the utility of differentiation platforms, namely the generation of Neural Progenitor Cells (NPCs) from human iPSCs, as a suitable strategy for the study of driver mutations and the mechanistic events underlying adult stem cell transformation towards a cancer stem cell phenotype. Here I describe the establishment of reprogramming methodologies for the modelling of brain tumours and glioma stem cell formation. Interestingly, cancer progression leads to the establishment of an embryonic gene expression signature in high-grade dedifferentiated tumours, which opens the possibility that, overexpression of defined genes results in the dedifferentiation of cancer cells to cancer stem cells. Identification of the mechanisms underlying cancer cell dedifferentiation to a CSC phenotype might open new venues for the development of targeted therapeutics. The work I pursued aimed for the generation of cellular platforms mimicking the cellular processes underlying the dedifferentiation of cancer cells to a stem cell phenotype. Controlled reprogramming upon overexpression of Oct4, SOX2, c-MYC and KLF4, the very same genes used to dedifferentiate somatic cells to an iPSC state, allows for the dedifferentiation of glioma cells to multipotent glioma stem cells in the absence of iPSC generation. Dedifferentiation to glioma stem-like cells resulted in increased malignancy and metabolic reprogramming. Together, these results highlight the potential of reprogramming strategies for studying the dynamic processes leading to glioma stem cell formation and pave new avenues for the development of cancer therapeutics.