The Niche

PTEN lessons from planaria

This one is by freelancer Simone Alves. We’ll have it up on Nature Reports next Thursday.

PTEN (phosphatase and tensin homolog) is an important tumour suppressor in humans, and its disruption contributes to a wide variety of cancers. The fact that it appears to negatively regulate the PI3K/Akt pathway, which controls cellular proliferation and differentiation, implies that it is important in adult tissue homeostasis; however, until now, its role in this process had not been fully explored. A study published this week in Disease Models & Mechanisms, from Alejandro Sánchez Alvarado at the University of Utah, in Salt Lake City, describes a new planarian model system to study the role of this tumour suppressor in tissue homeostasis. The team shows that the homolog’s function in stem cell regulation is highly conserved.

Planarians are small, nonparasitic flatworms that have a remarkable capacity for regeneration. They contain a large population of undifferentiated cells called neoblasts, which are considered adult stem cells because they constantly self-renew and produce differentiating daughter cells. Early in his career, Sánchez Alvarado used the simplicity of planarians to his advantage. “He almost single-handedly turned planarians into a system for studying stem cell biology,” says Sean Morrison, director of the University of Michigan Center for Stem Cell Biology, in Ann Arbor.

The Utah team found that planarians had two homologues of the human phosphatase and tensin homolog (PTEN) gene and, using RNA interference, discovered that planarians could survive with just one functioning gene. However, when both genes were knocked down, the team noticed cancer-like outgrowths on the flatworms, which proved to be lethal. This was a surprise to the researchers. “We got the mammalian phenotype, not the invertebrate phenotype that we expected,” says Sánchez Alvarado.

The loss of PTEN function caused general tissue disorganisation, with neoblasts overproliferating and adult cells losing signs of differentiation, which are both hallmarks of mammalian cancers. Normal regeneration and wound-healing processes were also lost, and expression of the oncoprotein Akt increased. What particularly interested Sánchez Alvarado was that a drug called rapamycin, which inhibits the mammalian target of rapamycin (mTOR) protein kinase in mammals, was able to largely sidestep the effects of the PTEN double knockdown in planarians without affecting normal physiological neoblast proliferation. He suggests that planarians may, in the future, be used to screen other potential cancer drugs.

“The discovery that PTEN and TOR regulate stem cell function and regeneration in planaria demonstrate that these remarkable animals use evolutionarily conserved mechanisms that are surprisingly similar to the mechanisms we observe in mammalian stem cells,” says Morrison. Indeed, Sánchez Alvarado is excited at the idea that planarians represent a system in which to model aspects of biology that have so far been inaccessible using other invertebrates. He hopes to go on to identify how functionally conserved other tumour suppressors might be. “These results further support the value of studies in planarians to discover regulatory mechanisms that could provide new insights into how the human body works and what goes wrong in the context of disease,” Morrison adds.

References

1. Oviedo, N. et al. Planarian PTEN homologs regulate stem cells and regeneration through TOR signalling. Dis. Models Mech . doi:10.1242/dmm.000117 (published online 2008).

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