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Dynamic cells linked to brain tumor growth and recurrence

Overview: Eliminating collagen 1 production in tumor cells allowed animal models of brain tumors to live longer.

Source: University of Michigan

Tumors are made up of many types of cells, both cancerous and benign. The specific complexity of the cells in brain tumors has been a trademark of the disease, one that makes treatment extremely difficult.

Although scientists have long known about the variety of cells in a brain tumor, the way these tumors grow is based on the understanding that the cells are static, immobile and relatively fixed.

But researchers at the University of Michigan’s Rogel Cancer Center have found that these aggressive tumors contain highly active cells that move through tissue in intricate patterns. In addition, the clusters of these elongated spindle-like cells found throughout the tumor, called “oncostreams,” serve as the basis for the behavior of cancer cells, which determine how tumors grow and invade normal tissue.

Pedro Lowenstein, MD, Ph.D., Richard C. Schneider Collegiate Professor of Neurosurgery and lead author of this study in nature communicationsays this organized growth makes brain tumors so unforgiving.

“Brain tumors are very lethal, less than 5% of patients live older than five years,” he said. “Unfortunately, recurrence is what patients eventually die from. They are operated on for their initial tumor, but the tumor always comes back within 12 to 18 months,” he said.

Lowenstein and his team, including Maria Castro, Ph.D., also found that overexpression of collagen 1, a protein produced by tumor cells, is essential for the growth and function of these structures.

“When we eliminated the production of collagen 1 from tumor cells, the animal models with brain tumors lived much longer. This step removes oncostreams from tumors and reduces the aggressive behavior of the tumor because the tumors need collagen 1 to move in the specific way we discovered,” Lowenstein said.

Lowenstein says this structure is likely present in other cancers as well. “Once people recognize that there are dynamic parts of the tumor and that they are related to tumor growth, eventual invasion and death, people are likely to localize oncostreams in other tumor models,” he said.

This shows tumor cells
Collagen 1, a protein produced by tumor cells, is essential for the growth and function of these tumor oncostreams. Credit: Pedro Lowenstein

To detect this previously unknown presence of oncostreams, the team collaborated with Todd Hollon, MD, assistant professor in the Michigan Medicine Department of Neurological Surgery, and Sebastien Motsch, Ph.D., associate professor of mathematics at Arizona State University, to use artificial intelligence methods to identify the structures in tissue.

“Essentially, we’ve shown images to a computer, and the computer eventually learns to recognize oncostreams,” explains Lowenstein.

Dismantling oncostreams through the removal of collagen 1 could be a new therapeutic target for the treatment of lethal brain tumors. “This study demonstrates the critical importance of continuing to explore the complicated extracellular matrix,” notes Andrea Comba, Ph.D., study researcher and lead author of the study.

“Based on this discovery, we propose targeting tumor collagen to disrupt oncostreams, and as a novel therapy for the treatment of brain glioma,” she said.

About this news about brain cancer research

Author: Anna Megdell
Source: University of Michigan
Contact: Anna Megdell – University of Michigan
Image: The image is attributed to Pedro Lowenstein

Original research: Open access.
Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as a useful target to disrupt tumor progressionby Pedro Lowenstein et al. nature communication

Also see

This shows DNA

Abstract

Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as a useful target to disrupt tumor progression

Intratumoral heterogeneity is a hallmark of glioblastoma that challenges the efficacy of the treatment. However, the mechanisms driving tumor heterogeneity and tumor cell migration remain poorly understood.

Herein, we present a comprehensive spatiotemporal study that aligns distinctive intra-tumor histopathological structures, oncostreams, with dynamic properties and a specific, useful, spatial transcriptomic signature.

Oncostreams are dynamic multicellular bundles 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 possibly the collective invasion of the normal brain. These bundles are defined by a specific molecular signature that governs their organization and function.

The structure and function of oncostreams is dependent on COL1A1 overexpression. Col1a1 is a central gene in the dynamic organization of glioma mesenchymal transformation and a potent regulator of glioma malignant behavior. inhibition of Col1a1 eliminates oncostreams, reprograms the malignant histopathological phenotype, decreases the 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.

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