Our research partners in the UK and Europe–Drs Hannah Brunsdon, Ralitsa R Madsen, Robert K. Semple, E. Elizabeth Patton, and more–just had a pre-print published detailing their work with Zebrafish and the PIK3CA gene–a project made possible by seed funding from CLOVES Syndrome Community!
For reference, a pre-print is a scientific or scholarly research paper shared publicly online before formal peer review and journal publication. They have also submitted the paper to a journal (PNAS) in the hopes it will get accepted for peer review, which will draw more eyes and attention to this team’s incredible work (and to CLOVES Syndrome/PROS!)
You can read the paper here: Mosaic PIK3CA-related overgrowth spectrum mutations cause non-cell autonomous vascular overgrowth and pan-lineage dysregulation at disease onset
And/or read the lay summary graciously provided by Dr. Hannah Brunsdon, below:
Funded by a generous grant from the CSC, we were able to show that we could develop a new zebrafish model of CLOVES. This allowed us to attract larger funding from the UK government, which would not have been possible without CSC support. Since then we have made good progress.
First, some background. Although zebrafish are “just” small stripy fish, they share more genes and cell types with us than you might expect. Zebrafish embryos are also transparent, allowing us to study them microscopically from a single cell through to adulthood. We can also easily change the genes of fish to match human disease, making them excellent tools for modelling diseases like CLOVES. This is why we have been using our fish to study how CLOVES emerges during early development, and to try to figure out new ways to block the process. This would be equivalent to watching a developing baby all the way from being a single cell, to track exactly when and where the first problems that turn into CLOVES appear.
So what have we found? We found that our model CLOVES fish developed misshapen and thickened blood vessels from very early development (equivalent to early stages in the womb), showing a range of severity similar to human disease. Surprisingly, we saw that overgrown blood vessels didn’t just contain CLOVES cells. Instead they were mostly ‘normal’ cells with CLOVES cells located nearby. This led us to think that CLOVES cells must exert unhealthy effects on normal cells from a distance, contributing to overgrowth. To test this further, we looked at all the genes turned on in CLOVES and normal cells from our model fish. Again, we found that small numbers of CLOVES cells have major effects on how other cells behave, with effects on how they develop and communicate, not just in blood vessels but in the whole fish.
Why is this useful to know? Well, now that we can see such strong evidence of downstream effects of CLOVES cells on the cells around them, we hope that we can block some of these with medicines eventually. This may open up a whole new way to attack the abnormal growth in CLOVES. Of course there are many steps needed before we get as far as new medicines, but this has been a great first step – all thanks to small, stripy fish, and CSC!