Like an orderly flock of migrating birds, researchers from the University of Michigan have discovered that glioma cells travel through brain tumors via self-assembled networks of "oncostreams."
In a study presented at a virtual conference on the "Evolving Tumor Microenvironment in Cancer Progression," held online January 11-12, 2021, by the American Association for Cancer Research (AACR), the researchers said they can now disassemble these molecular pathways in rodent and human gliomas by inhibiting a key gene, called collagen 1a1 or COL1A1, used to maintain the structure's integrity (Abstract PR005).
"Whether tumors are self-organizing or not has been discussed in the literature, but no strong evidence had been shown before," said Andrea Comba, PhD, a postdoctoral research fellow at the University of Michigan Medical School, who presented results at the conference. "We were able to provide strong data in support of the hypothesis that brain tumors are indeed self-organizing and that disrupting such self-organization could be of therapeutic value."
Added Pedro Lowenstein, MD, PhD, Professor of Neurosurgery and Cell and Developmental Biology at the University of Michigan and the study's principal investigator: "Brain tumors are not accumulations of cells, but self-organizing tissues. This implies the existence of a logic basis underpinning for the organization of these cells. Identifying this logic and then attempting to disassemble tumor self-organization will become a new treatment for tumors."
Examining Brain Tumors
Primary brain tumors are one of the most lethal of all cancers. In spite of surgery, radiotherapy and chemotherapy, overall survival has only inched forward in the last 30 years, with patients generally succumbing to their disease in 12-18 months post-diagnosis.
Based on these dismal statistics, researchers are trying to identify novel treatment approaches that would block the growth and spread of brain tumors. For their part, the University of Michigan team has turned to a previously unknown feature of gliomas called "oncostreams," essentially elongated malignant cells found in rodent and human gliomas that foster tumor growth, invasion, and the migration of non-migrating tumor cells.
As outlined in her talk, Comba said their team has studied oncostream structure, function, and molecular makeup in several experimental mouse models and human glioblastoma tumors. From histological sections of tumor from rodents and mice, the team identified oncostreams, essentially elongated malignant cells about 10-20 cells wide, of various lengths distributed throughout the tumor.
Based on their appearance, the team predicted they might represent cells moving in an organized fashion, which was later confirmed with the use of time-lapse advanced imaging techniques that caught this pattern of collective motion for the first time.
Some oncostreams moved in one direction, others more like a two-lane highway. The team proposed these highways stimulated the spread of slower-moving glioma cells and/or nontumor cells throughout the tumor mass, "reinforcing a potential role of oncostreams in determining spatial heterogeneity and remodeling of the tumor microenvironment."
Added Comba: "It was surprising to discover the large amount of cellular movement within tumors, and their capacity to self-organize into large-scale structures."
Genetic Discovery
Using genetically engineered glioma models, the team then showed that tumor aggressiveness was directly related to the density of cells in the oncostreams. From a large cohort of glioma diagnostic slides in The Cancer Genome Atlas, their results showed oncostreams present in 47 percent of grade 4 tumors and 8.6 percent in grade 3 tumors. They were completely absent in grade 2 tumors.
"As oncostreams also reached tumor borders, it is likely that they participate in glioma invasion," the team wrote in an abstract of their research. "Further, by placing slow moving glioma stems cells into oncostreams, we detected that these function as streams that distribute glioma cells throughout tumors."
Next, the team performed a molecular analysis of oncostreams using a laser microdissection microscope to dissect and separate oncostreams from surrounding tumor. Then, with the aid of next-generation sequencing and advanced bioinformatics algorithms, the team performed a molecular analysis of the structures.
Their analysis revealed a distinct transcriptome signature consisting of 43 genes essential for the structure and performance of the oncostreams. Four of these were overexpressed in more malignant tumors compared to less malignant tumors, with one gene-COL1A1-widely expressed.
To determine its importance in the assembly of oncostreams, the team inhibited COL1A1 activity, using a short hairpin RNA or small hairpin RNA (shRNA), an artificial RNA molecule with a tight hairpin turn that's used to silence target gene expression.
"Genetic inhibition of COL1A1 disassembled oncostreams, decreased glioma heterogeneity, and improved animal survival," the researchers wrote in their abstract.
Lowenstein said that the experimental method used to disrupt oncostreams in these studies could not be applied in the clinic. "However, it might be possible to use pharmacological inhibitors of collagen 1a1 production or nanoparticles based on therapies carrying specific siRNA (small interfering RNA) as potential treatments for tumors."
Next steps would include gaining a better understanding of the genetic makeup of oncostreams, both in cells and in animal models.
"This will provide molecular insights to inhibit oncostream formation in tumors, and thus reduce tumor progression and mortality," Lowenstein noted.
Warren Froelich is a contributing writer.