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Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies., Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.

Recent advances in in vitro culture technologies, such as adult stem cell-derived organoids, have opened up new avenues for the development of novel, more physiologic human cancer models. Such preclinical models are essential for efficient translation of basic cancer research into novel treatment regimens. We succeeded in growing organoids from a range of pediatric solid tumors, including Wilms’ tumors, renal cell carcinomas, and different types of rhabdoid tumors (i.e., AT/RT, MRT). Tumor organoids retain many characteristics of parental tumor tissue. For instance, Wilms’ tumor organoids retain the cellular heterogeneity of tumors, as they are composed of an intricate network of different cell types. Moreover, we demonstrate that tumor organoids are amenable to gene editing and high-throughput drug screens. In conclusion, our pediatric cancer organoids capture disease and tissue heterogeneity and provide a platform for basic cancer research, drug screening, and personalized medicine. Citation Format: Camilla Calandrini, Frans Schutgens, Rurika Oka, Thanasis Margaritis, Tito Candelli, Luka Mathijsen, Carola Ammerlaan, Ravian van Ineveld, Sepideh Derakhshan, Lars Custers, Philip Lijnzaad, Harry Begthel, Hinri Kerstens, Maarten Rookmaker, Marianne Verhaar, Patrick Kemmeren, Ronald de Krijger, Kathy Pritchard-Jones, Anne Rios, Marry van den Heuvel-Eibrink, Frank Holstege, Ruben van Boxtel, Hans Clevers, Jarno Drost. Patient-derived organoids in pediatric cancer research [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA27.