Summary: Researchers have identified a key molecule, miR-181d, that regulates the “chaos” within glioblastoma tumors. By administering this molecule, they successfully reduced the variability between cancer cells, making the tumor more susceptible to standard chemotherapy treatments.
Source: Brown University Health
Key Facts:
- The Problem: Glioblastoma tumors are composed of highly diverse (heterogeneous) cells, allowing some to survive treatment while others die.
- The Culprit: A DNA-repair protein called MGMT allows cells to fix chemo damage. Its production varies wildly between cells.
- The Discovery: A small molecule called miR-181d acts as a “master switch” for MGMT production.
- The Solution: Administering miR-181d stabilizes the tumor cells, making them behave uniformly and increasing the effectiveness of chemotherapy.
A groundbreaking study from Brown University Health researchers has identified a crucial factor that may help improve treatment for glioblastoma, one of the most aggressive and common forms of adult brain cancer. The findings, published November 10 in Cell Reports, reveal how differences among cells within a single tumor influence the cancer’s response to chemotherapy, and introduce a promising new therapy designed to tip the odds in the patients’ favor.
Glioblastoma is notoriously difficult to treat. One of the key reasons is that no two cells within the tumor behave exactly alike. Even inside one tumor, some cells may respond to treatment while others resist it, allowing the cancer to persist and grow. For decades, scientists have known that tumors are composed of diverse cells, but the biological forces driving these differences, and their impact on treatment, have remained elusive.
“Traditionally, researchers have focused on the overall behavior of a tumor by studying the average response across all the individual cells, using differences between the cells to interpret the average,” said senior author Clark Chen, MD, PhD, professor and director of the brain tumor program, department of neurosurgery at Brown University Health. “Our study fundamentally flipped that approach. Rather than focusing on the average response, we focused on the differences between individual cells within the same tumor, and what we found could change how we treat glioblastoma.”
Chen’s team discovered that a small molecule called miR-181d acts like a master switch that helps control how much of a DNA-repair protein called MGMT (short for Methyl-Guanine Methyl Transferase) each glioblastoma cell produces. MGMT is crucial because it allows cancer cells to fix the damage caused by chemotherapy, making them harder to kill. The problem is that not all tumor cells make the same amount of MGMT, some produce a lot, while others make very little. This uneven production means that while some cells die during treatment, others survive to fuel tumor growth.
When glioblastoma tumors are treated with chemotherapy, levels of miR-181d drop. This drop amplifies the differences among individual cells within the tumor, thereby allowing more cells to make more MGMT and survive treatment. The research team found that administering miR-181d into the tumor can reduce this effect, making the cancer cells behave more uniformly, and importantly, more likely to respond to chemotherapy.
“This is an exciting step forward,” commented Gatikrushna Singh, assistant professor of neurosurgery, University of Minnesota and one of the study’s key collaborators. “Scientifically, it helps explain why tumors maintain so much internal variability. Clinically, it opens the door to gene-therapy strategies that could be truly game-changing for many glioblastoma patients.”
The discovery has already led to the development of a new potential therapy aimed at improving patients’ responses to chemotherapy by stabilizing miR-181d levels within the tumor.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Glioblastoma Research Article:
- Author: Jessica Wharton
- Source: Brown University Health
- Contact: Jessica Wharton – Brown University Health
- Image: The image is credited to Neuroscience News
Original Research: “Single-cell heterogeneity of MGMT expression is regulated by miR-181d in glioblastoma” by Clark Chen et al. Cell Reports
DOI/URL : https://doi.org/10.1016/j.celrep.2025.116516
This study was a collaborative effort involving scientists from Brown University Health, the University of Minnesota, VisiCELL Medical Inc., Stanford University, and Johns Hopkins University.
*Co-authors of this study also include Gatikrushna Singh, Shilpi Singh, Iteeshree Mohapatra, Stefan Kim, Mayur Sharma, University of Minnesota; Johnny Akers, VisiCELL Medical Inc., Thien Nguyen, Stanford University; Efrosini Kokkoli, John Hopkins University; Eric Wong, Margot Martinez Moreno, Shobha Vasudevan, Sean E. Lawler, Wafik S. El-Deiry, Ziya Gokaslan, Brown University Health.
Abstract/Summary of original research:
Single-cell heterogeneity of MGMT expression is regulated by miR-181d in glioblastoma” by Clark Chen et al. Cell Reports
DOI/URL : https://doi.org/10.1016/j.celrep.2025.116516
Intratumoral heterogeneity plays a pivotal role in cancer evolution, providing the substrate for adaptation to selective pressures, including chemotherapy treatment. Here, we demonstrate that miR-181d modulates variability in methyl-guanine methyl transferase (MGMT) expression, contributing to this heterogeneity in glioblastoma, the most common form of adult primary brain tumor. Treatment with standard-of-care temozolomide (TMZ) chemotherapy triggers a feedforward loop that accelerates polyribonucleotide nucleotidyltransferase 1 (PNPT1)-dependent miR-181d degradation. This degradation requires the activation of ataxia-telangiectasia and Rad3-related (ATR) kinase. The degradation of miR-181d in glioblastoma cells increases the variance of MGMT expression in the cell population, contributing to acquired TMZ resistance. This resistance is suppressed by exogenously transfected miR-181d. These findings suggest that microRNA regulates intratumoral heterogeneity by modulating the transcriptional variability of key DNA repair enzymes, providing a compelling rationale for miRNA delivery as a platform for glioblastoma therapy.
