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

Autor: Comba A; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Faisal SM; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Dunn PJ; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Argento AE; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA., Hollon TC; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Al-Holou WN; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Varela ML; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Zamler DB; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Quass GL; Kresge Hearing Research Institute, Department of Otolaryngology-Head & Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Apostolides PF; Kresge Hearing Research Institute, Department of Otolaryngology-Head & Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Abel C 2nd; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Brown CE; Department of Hematology & Hematopoietic Cell Transplantation, National Medical Center, City of Hope, Duarte, CA, 91010, USA., Kish PE; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Ophthalmology & Visual Science, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Kahana A; Ophthalmology & Visual Science, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Kleer CG; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Motsch S; School of Mathematical and Statistical Sciences, Arizona State University, Tempe, AZ, 85287, USA., Castro MG; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Lowenstein PR; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. pedrol@umich.edu.; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA. pedrol@umich.edu.; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. pedrol@umich.edu.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. pedrol@umich.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jun 24; Vol. 13 (1), pp. 3606. Date of Electronic Publication: 2022 Jun 24.
DOI: 10.1038/s41467-022-31340-1
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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