Nature communications · 2024
Developmental basis of SHH medulloblastoma heterogeneity.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Gold Maxwell P, Ong Winnie, Masteller Andrew M, Ghasemi David R, Galindo Julie Anne, Park Noel R, Huynh Nhan C, Donde Aneesh, Pister Veronika, Saurez Raul A, Vladoiu Maria C, Hwang Grace H, Eisemann Tanja, Donovan Laura K, Walker Adam D, Benetatos Joseph, Dufour Christelle, Garzia Livia, Segal Rosalind A, Wechsler-Reya Robert J, Mesirov Jill P, Korshunov Andrey, Pajtler Kristian W, Pomeroy Scott L, Ayrault Olivier, Davidson Shawn M, Cotter Jennifer A, Taylor Michael D, Fraenkel Ernest
Аннотация
Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.