Reprogramming Tumor Cells and their Paracrine Interactions: A New Approach to Cancer Therapy

Cellular transformation is initiated by the activation of oncogenes and a closely associated developmental reprogramming of the epigenetic landscape. Transcription factors, regulators of chromatin states and microRNAs influence cell fates in development and stabilize the phenotypes of normal, differentiated cells. The same molecular mechanisms provide transforming properties to cancer, determine their paracrine cellular interactions in the tumor microenvironment and the potential of primary tumor cell to metastasize. We investigated if the state of transformation can be reversed to achieve the normalization of cellular properties. We used the genetically highly aberrant glioblastoma cells and investigated the effects exerted by the expression of the miR-302/367 cluster. The miR-302/367 cluster can promote the cellular reprogramming of human and mouse cells and contribute to the generation of iPSC. We found that the epigenetic reprogramming potential of the miR-302/367 cluster is able to “de-program” tumor cells, i.e. shift their gene expression pattern towards an alternative program associated with more benign cellular phenotypes. It suppressed transformation related proteins, e.g. the reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC, and the transcription factors POU3F2, SALL2 and OLIG2, required for the maintenance of glioblastoma stem like tumor propagating cells. It also diminished PI3K/AKT and STAT3 signaling, impeded colony formation in soft agar and cell migration. At the same time, the miR-302/367 cluster restored the expression of neuronal markers of differentiation. The suppression of pro-inflammatory cytokine secretion drastically affected the tumor microenvironment. miR-302/367 cluster expressing cells lose their ability to form tumors and to establish liver metastasis in nude mice. The process of “de-programing” of tumor cells could potentially become a new concept for cancer therapy.