PT  - JOURNAL ARTICLE
AU  - Andrea Comba
AU  - Syed M. Faisal
AU  - Patrick J. Dunn
AU  - Anna E. Argento
AU  - Todd C. Hollon
AU  - Wajd N. Al-Holou
AU  - Maria Luisa Varela
AU  - Daniel B. Zamler
AU  - Gunnar L Quass
AU  - Pierre F. Apostolides
AU  - Clifford Abel II
AU  - Christine E. Brown
AU  - Phillip E. Kish
AU  - Alon Kahana
AU  - Celina G. Kleer
AU  - Sebastien Motsch
AU  - Maria G Castro
AU  - Pedro R. Lowenstein
TI  - Spatiotemporal analysis of glioma heterogeneity reveals Col1A1 as an actionable target to disrupt tumor mesenchymal differentiation, invasion and malignancy
AID  - 10.1101/2020.12.01.404970
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2020.12.01.404970
4099  - http://biorxiv.org/content/early/2022/04/07/2020.12.01.404970.short
4100  - http://biorxiv.org/content/early/2022/04/07/2020.12.01.404970.full
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.