Targetable NOTCH1 rearrangements in reninoma

Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma

Targetable NOTCH1 rearrangements in reninoma

Abstract Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma

Targetable NOTCH1 rearrangements in reninoma

Acknowledgements: This project was funded by The Little Princess Trust (grant number CCLGA 2019 27) and the Wellcome Trust Grants (grants 206194; 108413/A/15/D; 223135/Z/21/Z). G.M. was supported by La Ligue Contre le Cancer and by Assistance Publique Hôpitaux de Paris. P.J. is supported by a grant from the Wellcome Trust to the Wellcome Sanger Institute, 296194 and a Cancer Research UK Programme Grant, C609/A27326. We thank Professor Freddy Ratke for sharing his expertise on NOTCH1 and Professor Jan Danser for helping us access raw sequencing data of his reninoma study. We thank the clinical teams involved in the care of patients, in particular Professor Imran Mushtaq, Mrs Eileen Brennan and Dr Lauren Roe of Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. We are indebted to our patients and their families for participating in this research.Funder: The Little Princess Trust (grant number CCLGA 2019 27) and the Wellcome Trust Grants (grants 206194; 108413/A/15/D; 223135/Z/21/Z).Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma

Targetable NOTCH1 rearrangements in reninoma

Acknowledgements: This project was funded by The Little Princess Trust (grant number CCLGA 2019 27) and the Wellcome Trust Grants (grants 206194; 108413/A/15/D; 223135/Z/21/Z). G.M. was supported by La Ligue Contre le Cancer and by Assistance Publique Hôpitaux de Paris. P.J. is supported by a grant from the Wellcome Trust to the Wellcome Sanger Institute, 296194 and a Cancer Research UK Programme Grant, C609/A27326. We thank Professor Freddy Ratke for sharing his expertise on NOTCH1 and Professor Jan Danser for helping us access raw sequencing data of his reninoma study. We thank the clinical teams involved in the care of patients, in particular Professor Imran Mushtaq, Mrs Eileen Brennan and Dr Lauren Roe of Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. We are indebted to our patients and their families for participating in this research.Funder: The Little Princess Trust (grant number CCLGA 2019 27) and the Wellcome Trust Grants (grants 206194; 108413/A/15/D; 223135/Z/21/Z).Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma

Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of WT1 kidney disease

WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of the vascular factors Vegfa and Neuropilin-1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned media from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium were exposed to Wt1R394W/+ podocyte media. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease