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Stem Cell Biology, Disease Mechanisms

The “eternal youth” of cancer cells

Tumors grow indefinitely, but how cancer cells achieve immortality is unclear. The Knoblich lab discovered that asymmetric accumulation of the non-coding RNA Cherub in undifferentiated neural stem cells disrupts the localization and function of proteins that regulate the temporal clock. Their recent paper published in ELife provides a new critical link between the temporal identity of a stem cell and its proliferation control.

Tumors arise from unconstrained growth of immortal cancer cells, but how do cancer cells become immortal in the first place? To answer this question, the Knoblich lab investigates tumorigenesis in the fruit fly Drosophila. In fly larvae, neural stem cells typically divide asymmetrically, giving rise to a stem cell that replenishes the stem cell pool and an intermediate neural progenitor that ultimately produces specialized neurons. Loss of the tumor suppressor Brat causes these neuroblasts to divide symmetrically, producing two tumorigenic stem cells that divide indefinitely.

Knoblich’s group asked why tumor stem cells proliferate without restrictions, unlike normal neuroblasts. During normal development, neuroblasts transit through distinct temporal identities and eventually exit the cell cycle. The scientists found that some tumor neuroblasts, however, never reach the late identity: loss of brat ‘halts’ the temporal clock and traps them in an early stage.

“We found that the mechanism of this break involves a non-coding RNA called cherub, that is highly expressed and upregulated in tumor stem cells. Interestingly, loss of cherub reduced tumor growth in brat flies – increasing their lifespan – but did not affect normal flies;” says Lisa Landskron, a VBC PhD student and first author of the paper.

In normal flies, the RNA-binding protein Staufen localizes cherub to the basal plasma membrane in dividing neuroblasts, leading to its exclusive enrichment in neural progenitors. Cherub levels then decrease as neurons differentiate. Upon loss of brat, cherub still segregated into one cell after division. The cell with high cherub levels becomes a tumor neuroblast instead of producing a neural progenitor.  “Our findings reveal a previously unknown mechanism of cancer cell immortality, via disruption of stem cell aging. Importantly, inactivation of cherub ‘cured’ brat flies of cancer without affecting normal flies. Identifying such a specific therapeutic target and treatment strategy for human cancer could be the holy grail of cancer research,” says Jürgen Knoblich.


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