The mechanosensor Filamin A/Cheerio promotes tumourigenesis via specific interactions with components of the cell cortex

Cancer development has been linked to aberrant sensing and interpretation of mechanical cues and force-generating properties. Here, we show that upregulation of the actin crosslinking protein Cheerio (Cher), the fly ortholog of Filamin A (FLNA), and the conformation of its mechanosensitive region (MSR) are instrumental to the malignancy of polarity-deficient, Ras-driven tumours in Drosophila epithelia. We demonstrate that impaired growth and cytoskeletal contractility of tumours devoid of cher can be rescued by stimulating myosin activity. Profiling the Cher interactome in tumour-bearing imaginal discs identified several components of the cell cortex, including the beta-heavy Spectrin Karst (Kst), the scaffolding protein Big bang (Bbg), and 14-3-3 epsilon. We show that Cher binds Bbg through the MSR while the interaction with 14-3-3 epsilon and Kst is MSR-independent. Importantly, our genetic studies define Bbg, Kst, and 14-3-3 epsilon as tumour suppressors. The tumour-promoting function of Cher thus relies on its capacity to control the contractile state of the cytoskeleton through interactions with myosin and specific components of the cell cortex.

Automated summary

Cancer development is affected by aberrant sensing and interpretation of mechanical cues and force-generating properties. In this study, the researchers identified the actin crosslinking protein Cheerio (Cher) and its mechanosensitive region (MSR) as instrumental to the malignancy of Ras-driven tumors in Drosophila epithelia. They showed that stimulating myosin activity can rescue the impaired growth and cytoskeletal contractility of cher-deficient tumors. The study also found that Cher interacts with several components of the cell cortex, including Bbg, Kst, and 14-3-3 epsilon, which were identified as tumor suppressors. This highlights the importance of Cher in controlling the contractile state of the cytoskeleton through interactions with myosin and specific components of the cell cortex.