NEW YORK – A research team from Wuhan University, BGI Research, and the Chinese Academy of Sciences has teased out the regulatory proteins at play within four distinct cellular states previously reported in glioblastoma (GBM) tumors.
Their results, published in the journal Science Advances on Friday, suggest the possibility of tackling the common and deadly form of brain cancer with a dual-target treatment.
"This study reveals distinct characteristics of tumor cells across tumor regions and surrounding normal tissues, focusing on epigenetics, transcriptomics, and associated regulation," co-senior and co-corresponding author Liang Chen, a researcher affiliated with BGI Research and Wuhan University, said in an email. "It highlights the importance of considering residual tumor cells when designing treatment strategies."
For their new analysis, the researchers turned to single-nucleus RNA sequencing and single-nucleus ATAC-seq to assess gene expression and regulatory features, respectively, in nuclei from up to 100,565 cells in paired tumor core and peritumoral brain regions from five individuals with GBM.
The work offered a look at the molecular basis of the heterogeneity described in and around GBM tumors. Four subtypes of GBM have been described in prior studies, and a paper published in Cell in 2019 spelled out four heterogeneous cellular states that turn up within GBM tumors: neural progenitor-like cells, oligodendrocyte progenitor-like cells, astrocyte-like cells, and mesenchymal-like cells.
In their new study, the investigators teased out features found in tumor core cells infiltrating the area surrounding the tumor, finding dynamic gene expression features in the infiltration zone and similarities between the infiltrating cells and oligodendrocyte progenitor cells.
"Previous studies have identified infiltrating tumor cells, but detailed analysis was limited by technical challenges in isolating these cells from surrounding normal tissues," Chen explained, noting that single-cell technologies have made it possible to get a much broader look at the infiltrating cells, "enabling a deeper analysis of their heterogeneity, dynamic cellular states, and complementary regulon activities across tumor and normal regions."
The team also went on to flag specific transcription factors and regulatory regions with apparent ties to the distinct features of different GBM regions. They also identified diverse alterations that argued against the expected effectiveness of treatments targeting specific genetic changes or stem-like cell subsets.
"Together, our work reveals marked molecular alterations of infiltrated GBM cells and a synergy of combination therapy targeting intratumor heterogeneity in and distal to GBM," the authors wrote.
In particular, the team flagged two potential treatment targets: activator protein 1 (AP-1), which turns up across GBM cellular states but showed diminished activity in the peritumoral region relative to the tumor core, and a transcription factor called BACH1 that had lower activity in the tumor core and increasing activity in the peritumoral brain area.
That pattern pointed to a potential therapeutic strategy that involved targeting both AP-1 and BACH1 in GBM — an approach that showed promise in the researchers' subsequent experiments using mouse models of GBM, where the combined treatment approach stretched out survival times.
"Our findings provide a framework for region-specific tumor studies and suggest a potential combination therapy targeting AP-1 and BACH1 for glioblastoma (GBM)," Chen said. "This approach may not only improve GBM treatment but also offer insights into therapies for other diffuse tumors."
Still, Chen emphasized the need for further research to expand such analyses on larger sample sets and across more GBM regions, leading to a comprehensive picture of GBM growth, spread, and relapse features with a view to better treating the disease.
"Our data suggest that the cellular state changes as tumor cells disseminate or that cells in a specific state are more prone to invade neighboring areas," the authors wrote. "Therefore, to fully understand the cellular states of tumor cells continuously in space and deduce the invasion mechanisms, collection of transcriptome and regulatory information for GBM cells at regions between [the tumor core] and [peritumoral brain region], accompanied by characterizing the microenvironment from more patients, is needed."