Recent Advances in Pineoblastoma Research: Molecular Classification, Modelling and Targetable Vulnerabilities

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 720 - 720

Published: Feb. 20, 2025

Pineoblastoma (PB) is a rare yet lethal pediatric brain cancer of the pineal gland, small endocrine organ that secretes melatonin to regulate circadian rhythm. For PB patients ≤5 years age, overall survival rate approximately 15%; metastatic incurable. Standard treatment, including surgical resection, radiation, and systemic chemotherapy, improves but compromises neurocognitive function. A better understanding disease generation preclinical models may enable re-evaluation previous clinical trials, development precision therapeutic strategies improve patient outcome. Over past 5 years, has been recognized include several major subtypes driven by (i) loss microRNA processing factors DICER DROSHA characterized relatively good prognosis; (ii) retinoblastoma tumor suppressor RB1; (iii) amplification or induction cMYC protooncogene, with latter two exhibiting exceedingly poor prognosis. Recently, mouse for (RB1-, DICER1- DROSHA-) except MYC- have established. This progress, disease, cell origin, progression, role autophagy, targetable vulnerabilities, holds promise novel combat each subtype this childhood malignancy.

Language: Английский

Spatial single cell transcriptomic analysis of a novel DICER1 Syndrome GEMM informs the cellular origin and developmental hierarchy of associated sarcomas

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 5, 2024

Abstract DICER1 syndrome predisposes children and young adults to tumor development across various organs. Many of these cancers are sarcomas, which uniquely express the RNase IIIb domain-deficient form exhibit consistent histological molecular similarities regardless their anatomical origins. To uncover cellular origin developmental hierarchy, we established a lineage-traceable genetically engineered mouse model that allows for precise activation Dicer1 mutations in Hic1 + mesenchymal stromal cells. This resulted renal tumors closely mirroring human sarcoma histologically molecularly. Single-cell transcriptomics coupled with targeted spatial gene expression analysis revealed progenitor population marked by Pdgfra , Dpt Mfap4, corresponding universal fibroblasts steady-state kidneys. These fibroblastic progenitors capacity undergo rhabdomyoblastic differentiation or transition highly proliferative anaplastic sarcoma. Investigation patient samples identified analogous cell states. study uncovers provides faithful mechanistic investigation therapeutic within rhabdomyosarcoma spectrum.

Language: Английский