RT Journal Article
SR Electronic
T1 Spatiotemporal analysis of glioma heterogeneity reveals Col1A1 as an actionable target to disrupt tumor mesenchymal differentiation, invasion and malignancy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.01.404970
DO 10.1101/2020.12.01.404970
A1 Andrea Comba
A1 Syed M. Faisal
A1 Patrick J. Dunn
A1 Anna E. Argento
A1 Todd C. Hollon
A1 Wajd N. Al-Holou
A1 Maria Luisa Varela
A1 Daniel B. Zamler
A1 Gunnar L Quass
A1 Pierre F. Apostolides
A1 Clifford Abel II
A1 Christine E. Brown
A1 Phillip E. Kish
A1 Alon Kahana
A1 Celina G. Kleer
A1 Sebastien Motsch
A1 Maria G Castro
A1 Pedro R. Lowenstein
YR 2022
UL http://biorxiv.org/content/early/2022/04/07/2020.12.01.404970.abstract
AB Intra-tumoral heterogeneity and diffuse infiltration are hallmarks of glioblastoma that challenge treatment efficacy. However, the mechanisms that set up both tumor heterogeneity and invasion remain poorly understood. Herein, we present a comprehensive spatiotemporal study that aligns distinctive intra-tumoral histopathological structures, oncostreams, with dynamic properties and a unique, actionable, spatial transcriptomic signature. Oncostreams are dynamic multicellular fascicles of spindle-like and aligned cells with mesenchymal properties, detected using ex vivo explants and in vivo intravital imaging. Their density correlates with tumor aggressiveness in genetically engineered mouse glioma models, and high-grade human gliomas. Oncostreams facilitate the intra-tumoral distribution of tumoral and non-tumoral cells, and the invasion of the normal brain. These fascicles are defined by a specific molecular signature that regulates their organization and function. Oncostreams structure and function depend on overexpression of COL1A1. COL1A1 is a central gene in the dynamic organization of glioma mesenchymal transformation, and a powerful regulator of glioma malignant behavior. Inhibition of COL1A1 eliminated oncostreams, reprogramed the malignant histopathological phenotype, reduced expression of the mesenchymal associated genes, induced changes in the tumor microenvironment and prolonged animal survival. Oncostreams represent a novel pathological marker of potential value for diagnosis, prognosis, and treatment.Competing Interest StatementThe authors have declared no competing interest.