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Cooperation Among Pediatric Brain Cancer Tumor Cell Subpopulations Boosts Tumorigenic Ability

NEW YORK (GenomeWeb) – Tumor subpopulations found within pediatric brain cancers like glioblastoma and diffuse intrinsic pontine glioma can cooperate to increase their tumorigenic and treatment resistance abilities.

Because of their high heterogeneity, these pediatric brain cancers are difficult to treat, and the average survival for pediatric glioblastoma patients is about a year and diffuse intrinsic pontine glioma is nine months.

A team led by researchers at the Institute of Cancer Research in London analyzed whole-genome and exome sequencing data from 142 pediatric glioblastoma and diffuse intrinsic pontine glioma cases to evaluate the extent of their tumor heterogeneity. As they reported today in Nature Medicine, the researchers found that most tumors harbored between three and 10 subclones and that certain subclones increased other cells' ability to invade and migrate.

"These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development," senior author Chris Jones from ICR and his colleagues wrote in their paper. "Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments."

The researchers re-analyzed a set of recently published glioblastoma and diffuse intrinsic pontine glioma cases that had undergone whole-genome or exome sequencing. For each, they calculated the cancer cell fraction for SNVs and indels, while accounting for tumor cell percentages, ploidy, copy-number alterations, and loss of heterozygosity. Almost all the cases had a complex subclonal architecture with multiple co-dominant subclonal populations, the researchers found.

Using the bioinformatics tool EXPANDS, they calculated the number of subclones in each sample to find they harbored a median six subclones, with most tumors having between three and 10 subclones. For the eight cases for which the researchers had both pre- and post-treatment samples, they noted differences in the proportion of subclone populations in response to treatment.

Jones and his colleagues also teased out single cells from tumors to grow up under stem cell conditions. One single-cell-derived colony that formed harbored a mutation in its histone H4 methyltransferase KMT5B gene, which they then also noticed in another pediatric glioblastoma case, indicating that it is not an isolated mutation.

Wild-type cells and KMT5B-mutated cells did not differ from each other in terms of morphology or immunophenotype, the researchers noted. Still, mutant cells had decreased H4K20me2 and were more sensitive to PARP inhibitors. But, cell cultures of mixed mutant and wild-type cells were as insensitive to treatment as heterogeneous bulk cells, the researchers reported.

RNA sequencing of the KMT5B mutant cells revealed they had increased expression of a number of genes associated with remodeling the extracellular matrix. This, the researchers said, could account for why wild-type KMT5B cells are less invasive and migratory than the mutant ones. But when wild-type cells are mixed with medium obtained from bulk cell cultures, they gained that ability.

This suggested to the researchers that the two subpopulations affected the others' ability to withstand treatment and become more invasive — and they found that the KMT5B mutant cells expressed a chemokine that seems to influence the wild-type cells' migratory abilities. They added that the idea of 'cooperative invasion' had previously been identified in melanoma.

"Understanding how the derived subclones interact and adapt to the tumor microenvironment, and to therapy, will be a key requirement for maximizing patient benefit from existing treatment options," the researchers wrote.