Micro-environmental control of tumor differentiation and invasiveness

Sammanfattning: The transforming growth factor β (TGFβ) family participates in embryonic development and adult tissue homeostasis. In early stages of tumorigenesis, TGFβ promotes cell cycle arrest and apoptosis; however, in advanced malignancies, TGFβ promotes tumor cell migration and metastasis via the induction of epithelial-tomesenchymal transition (EMT). A new aspect of the regulation of TGFβ signalling is the participation of non-coding RNAs, molecules that are not translated into proteins but are nevertheless important regulators of gene expression. The expression of the long non-coding RNA LINC00707 was identified being down-regulated by TGFβ by engaging the transcription factor KLF6. LINC00707 resides in the cytoplasm where it interacts with and sequesters the Smad proteins, which mediate TGFβ signals. Thus, when TGFβ signaling downregulates LINC00707, the Smad complex is free to enter the nucleus and regulate its target genes implicated in the EMT process. It is also important to consider the biology of cells in their microenvironment. The growth of solid tumors leads to regional deprivation of nutrients within a tumor. Glutamine deprivation in mesenchymal and epithelial hepatocellular carcinoma cell lines showed a large change in gene expression related to TGFβ signaling in cells adapted to glutamine deprivation, suggesting a dependence of TGFβ signaling on glutamine metabolism. In mesenchymal cells, we observed a mesenchymal-to-epithelial transition associated with reduced metabolic activity and a reduced generation of reactive oxygen species. Mitochondrial reactive oxygen species are known for their capacity to regulate various signalling pathways associated with diverse cellular responses. This work also identified the polarity protein Par3 as a negative regulator of mitochondrial activity in glioblastoma cells. Moreover, Par3 leads to suppressed invasiveness and sustained clonogenicity of glioblastoma cells.In summary, this work describes novel regulatory mechanisms that affect different aspects of cancer biology in both epithelial (carcinoma) and nonepithelial (glial) tumor cells. A central component that unifies these new mechanisms of cancer cell regulation is the TGFβ signaling pathway. In addition to its novel findings, this work opens several questions whose investigation can provide deeper mechanistic understanding of the action of the key RNAs or proteins analysed in this thesis.