The fundamental principles defining how cell state transitions are regulated along a tumour lineage to determine its cellular composition remain unclear. Here, we investigate how such transitions are controlled in a reductionist hierarchical brain tumour model. Quantitative analysis of 3D transition maps revealed that the differentiation of cancer stem cells (CSCs) into transit amplifying progenitors (TAPs) depends on the identity of their immediate neighbours. This is embodied in a transition rule that quantitatively predicts the probability to differentiate as a function of the proportion of TAP neighbours. Integrated into 3D simulations of tumour growth, this rule spontaneously recapitulates spatial segregation of CSCs in clusters and their stable proportion. We further show in vivo that CSC clustering protects the CSC pool from depletion driven by TAPs. We identify an EGFR-mediated relay mechanism that propagates the CSC-to-TAP transition across CSC clusters. In CSCs, the LRIG1-like EGFR inhibitor Kekkon1 dampens this propagation, ensuring continuous replenishment of the CSC pool. Collectively, these findings show how local fate regulation drives emergent segregation which in turn constrains CSC differentiation dynamics. This provides a conceptual framework to understand and exploit the tumour’s intrinsic differentiation potential by manipulating the determinants of its system-level features. ### Competing Interest Statement The authors have declared no competing interest. Turing Centre for Living Systems (CENTURI) La Ligue Contre le Cancer, https://ror.org/00rkrv905, Equipe Labellisée LIGUE 2025 Fondation pour la Recherche Médicale, ANR-24-EXCI-0001, ANR-24-EXCI-0002, ANR-24-EXCI-0003, ANR-24-EXCI-0004, ANR-24-EXCI-0005 Agence Nationale de la Recherche under the France 2030 program, ANR-24-EXCI-0001, ANR-24-EXCI-0002, ANR-24-EXCI-0003, ANR-24-EXCI-0004, ANR-24-EXCI-0005 Centre South-ROCK, INCa-Cancer_18695

This was a terrific discussion with Eric about my new biography of Francis Crick.

Written by Howard Chabner, Board Vice Chair, and shared on behalf of the entire FSHD Society Board of Directors The Board of Directors of the FSHD Society is deeply saddened to announce that Dan Perez...

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It is with great sadness that the University shares the news of the death of Professor Sir John Gurdon, founder of the Gurdon Institute.

Biochemistry; Cell biology; Developmental biology; Computational bioinformatics

Double Homeobox 4 (DUX4) is a potent transcription factor encoded by a retrogene mapped in D4Z4 repeated elements on chromosome 4q35. DUX4 has emerged as pivotal in the pathomechanisms of facioscapulo...

Targeting histone deacetylases (HDACs) alone has shown limited success in solid tumours. Here, authors report that the HDAC1/2 inhibitor romidepsin confers responsiveness to receptor tyrosine kinase inhibitors, with enhanced therapeutic effects in models of hepatocellular carcinoma, leading to tumour regression and an immune-stimulatory profile.

With age and disease, skeletal muscle is progressively lost and replaced by fibrotic scar and intramuscular adipose tissue (IMAT). While strongly corr…

Chromatin ist nicht unbeweglich. Es handelt sich um ein hochdynamisches Material, dessen 3D-Struktur zentrale genomische Prozesse – von der Transkription bis zur DNA-Reparatur – steuert. Doch wie verhält sich Chromatin als Material – als Flüssigkeit, Feststoff oder viskoelastisches Gel –, um diese Funktionen in lebenden Zellen auszuführen? Ohne eine Antwort auf diese Frage können wir nicht vollständig verstehen, wie Chromatin bei Krankheiten gestört wird.