4. How PIWI proteins regulate intestinal stem cell proliferation and cancer

How do stem cells control their proliferation to maintain healthy tissues, and how are these mechanisms exploited by cancer cells? Our recent work uncovered an unexpected role for PIWI proteins, a family of RNA-binding proteins best known for protecting the germline genome against transposons, in regulating intestinal stem cell proliferation in Drosophila and human colorectal cancer organoids (Bellec, Hayashi#, and Cordero#, 2026, Cell Reports).

In the germline, PIWI proteins typically work with small RNAs called piRNAs to recognise and silence transposons. However, we discovered that the Drosophila PIWI protein Aubergine (Aub) promotes intestinal stem cell proliferation following tissue damage, apparently independently of its conventional piRNA-mediated functions. Rather than silencing transposons, Aubergine facilitates the translation of a specific subset of messenger RNAs, revealing an unexpected role for PIWI proteins in regulating protein production during tissue regeneration.

Our findings raise an intriguing question: how have proteins best known for genome defence acquired additional roles in controlling stem cell behaviour? The observation that PIWI proteins also influence the growth of human colorectal cancer organoids suggests that these functions may have broader relevance to tissue regeneration and cancer biology.

In this project, we aim to uncover the molecular mechanisms by which Aubergine regulates mRNA translation and stem cell proliferation. We will investigate how Aubergine selects its target mRNAs, identify the molecular partners involved in its activity, and explore how this regulatory mechanism contributes to intestinal regeneration. Ultimately, we seek to understand how PIWI proteins coordinate RNA regulation with stem cell behaviour, and whether related mechanisms are exploited by cancer cells.

Techniques: Molecular biology and biochemistry, Drosophila genetics, cell type-specific gene manipulation using GAL4/UAS and RNAi, immunohistochemistry, fluorescence microscopy, RNA sequencing, and analysis of RNA translation.