The asymmetrically segregating lncRNA cherub is required for transforming stem cells into malignant cells

Autor: Ilka Reichardt, Jonas Steinmann, Victoria Steinmann, Anne-Sophie Laurenson, Thomas R Burkard, Heike Harzer, François Bonnay, Lisa Landskron, Heinrich Reichert, Jürgen A. Knoblich
Rok vydání: 2018
Předmět:
Zdroj: eLife
eLife, Vol 7 (2018)
ISSN: 2050-084X
DOI: 10.7554/eLife.31347
Popis: Tumor cells display features that are not found in healthy cells. How they become immortal and how their specific features can be exploited to combat tumorigenesis are key questions in tumor biology. Here we describe the long non-coding RNA cherub that is critically required for the development of brain tumors in Drosophila but is dispensable for normal development. In mitotic Drosophila neural stem cells, cherub localizes to the cell periphery and segregates into the differentiating daughter cell. During tumorigenesis, de-differentiation of cherub-high cells leads to the formation of tumorigenic stem cells that accumulate abnormally high cherub levels. We show that cherub establishes a molecular link between the RNA-binding proteins Staufen and Syncrip. As Syncrip is part of the molecular machinery specifying temporal identity in neural stem cells, we propose that tumor cells proliferate indefinitely, because cherub accumulation no longer allows them to complete their temporal neurogenesis program.
eLife digest Many biological signals control how cells grow and divide. However, cancer cells do not obey these growth-restricting signals, and as a result large tumors may develop. Recent experiments have suggested that stem cells – the precursors to the different types of specialized cells found in the body – are particularly important for generating tumors. A stem cell normally divides unequally to form a self-renewing cell and a more specialized cell (often a progenitor cell that will give rise to increasingly specialized cell types). The timing of when the specialization occurs can be key to guiding the ultimately produced cell progenies to their final identity. However, in a tumor cells can retain the ability to self-renew. Ultimately, the resulting ‘tumor stem cells’ become immortal and proliferate indefinitely. It is not fully understood why this uncontrolled proliferation occurs. Just like mammals (including humans), fruit flies can develop tumors. Some of the DNA mutations responsible for tumor development were already identified in flies as early as in the 1970s. This has made fruit flies a well-studied model system for uncovering the principle defects that cause tumors to form. Landskron et al. have now studied the neural stem cells found in brain tumors in fruit flies. Additional DNA mutations were not responsible for these cells becoming immortal. Instead, certain RNA molecules – products that are ‘transcribed’ from the DNA – were present in different amounts in tumor cells. The RNA that showed the greatest increase in tumor cells is a so-called long non-coding RNA named cherub. This RNA molecule has no important role in normal fruit flies, but is critical for tumor formation. Landskron et al. found that during cell division cherub segregates from the neural stem cells to the newly formed progenitor cells, where it breaks down over time. Progenitor cells that contain high levels of cherub give rise to tumor-generating neural stem cells. At the molecular level, cherubhelps two proteins to interact with each other: one called Syncrip that makes the neural stem cells take on a older identity, and another one (Staufen) that tethers it to the cell membrane. By restricting Syncrip to a particular location in the cell, cherub alters the timing of stem cell specialization, which contributes to tumor formation. Overall, the results presented by Landskron et al. reveal a new role for long non-coding RNAs: controlling the localization of the proteins that determine the fate of the cell. They also highlight a critical link between the timing of stem cell development and the proliferation of the cells. Further work is now needed to test whether the same control mechanism works in species other than fruit flies.
Databáze: OpenAIRE
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