Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression.
Andrea CombaSyed Mohd FaisalPatrick J DunnAnna E ArgentoTodd C HollonWajd N Al-HolouMaría Luisa VarelaDaniel B ZamlerGunnar L QuassPierre F ApostolidesClifford AbelChristine E BrownPhillip E KishAlon KahanaCelina G KleerSebastien MotschMaria Graciela CastroPedro R LowensteinPublished in: Nature communications (2022)
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.
Keyphrases
- cell migration
- high grade
- single cell
- induced apoptosis
- stem cells
- bone marrow
- poor prognosis
- cell cycle arrest
- high resolution
- genome wide
- endothelial cells
- low grade
- endoplasmic reticulum stress
- cell death
- gene expression
- rna seq
- signaling pathway
- oxidative stress
- long non coding rna
- risk assessment
- genome wide identification
- copy number
- single molecule
- pi k akt
- combination therapy
- smoking cessation
- climate change
- fluorescence imaging
- subarachnoid hemorrhage