Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression

Andrea Comba, Syed M. Faisal, Patrick J. Dunn, Anna E. Argento, Todd C. Hollon, Wajd N. Al-Holou, Maria Luisa Varela, Daniel B. Zamler, Gunnar L. Quass, Pierre F. Apostolides, Clifford Abel, Christine E. Brown, Phillip E. Kish, Alon Kahana, Celina G. Kleer, Sebastien Motsch, Maria G. Castro and Pedro R. Lowenstein ()
Additional contact information
Andrea Comba: University of Michigan Medical School
Syed M. Faisal: University of Michigan Medical School
Patrick J. Dunn: University of Michigan Medical School
Anna E. Argento: University of Michigan Medical School
Todd C. Hollon: University of Michigan Medical School
Wajd N. Al-Holou: University of Michigan Medical School
Maria Luisa Varela: University of Michigan Medical School
Daniel B. Zamler: University of Michigan Medical School
Gunnar L. Quass: University of Michigan Medical School
Pierre F. Apostolides: University of Michigan Medical School
Clifford Abel: University of Michigan Medical School
Christine E. Brown: City of Hope
Phillip E. Kish: University of Michigan Medical School
Alon Kahana: University of Michigan Medical School
Celina G. Kleer: University of Michigan Medical School
Sebastien Motsch: Arizona State University
Maria G. Castro: University of Michigan Medical School
Pedro R. Lowenstein: University of Michigan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: Abstract Intra-tumoral heterogeneity is a hallmark of glioblastoma that challenges treatment efficacy. However, the mechanisms that set up tumor heterogeneity and tumor cell migration remain poorly understood. Herein, we present a comprehensive spatiotemporal study that aligns distinctive intra-tumoral histopathological structures, oncostreams, with dynamic properties and a specific, 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 potentially the collective 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 eliminates oncostreams, reprograms the malignant histopathological phenotype, reduces expression of the mesenchymal associated genes, induces changes in the tumor microenvironment and prolongs animal survival. Oncostreams represent a pathological marker of potential value for diagnosis, prognosis, and treatment.

Date: 2022
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DOI: 10.1038/s41467-022-31340-1

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