A recent study shows that four transcription factors (TFs) dictate reprogramming of human differentiated glioblastoma cells into stem-like cells that can give rise to tumors in animals, as cancer-propagating cells do in human glioblastoma. The findings point toward a unidirectional, but potentially plastic, cellular hierarchy in glioblastoma (Cell 157, 1–15, 2014).

Mario Suvà and his colleagues derived both stem-like propagating tumor cells and differentiated tumor cells from human proneuronal glioblastomas. By comparing their epigenetic signatures, the authors identified several TFs that are differently expressed and direct the phenotypic state of the stem-like cells. A cocktail of the TFs SOX2, OLIG2, POU3F2 and SALL2 is sufficient to reprogram differentiated glioblastoma cells into stem-like cells with unlimited self-renewal that can propagate tumors in mice and show epigenetic characteristics of tumor-propagating cells from patients. These four TFs and the associated epigenetic circuits were also found in a small population of cells from fresh human primary glioblastoma that express a stem cell marker, validating the relevance of the results in human tumors.

Credit: CNRI / Science Source

A key target of this core set of TFs is a histone demethylase complex that may be a candidate therapeutic target to induce death in stem-like tumor cells, which are usually drug resistant. Future studies should confirm this hierarchical model in other subtypes of glioblastoma.