Summary: Researchers at Virginia Tech’s Fralin Biomedical Research Institute have developed a lab-designed peptide, JM2, that shows promise for preventing glioblastoma recurrence by targeting the tumor’s most treatment-resistant cells. The team found that glioblastoma stem-like cells depend on an interaction between the protein connexin 43 and microtubules, and JM2 disrupts this interaction.
In laboratory experiments JM2 selectively killed glioblastoma stem-like cells while sparing healthy brain cells, and in animal studies it markedly slowed tumor regrowth. These results point to a peptide-based strategy that attacks the cells responsible for tumor recurrence after standard therapies.
Key Facts:
- Connexin 43 Targeting: JM2 interferes with connexin 43’s interaction with microtubules, undermining a mechanism that supports glioblastoma stem-like cells.
- Selective Toxicity: JM2 is cytotoxic to glioblastoma stem-like cells but does not harm healthy brain cells in the models tested.
- Tumor Suppression: In preclinical models, JM2 reduced tumor regrowth following standard treatment, supporting its potential to slow recurrence.
Source: Virginia Tech
A lab-designed peptide developed and characterized by scientists at Virginia Tech’s Fralin Biomedical Research Institute at VTC could represent a meaningful advance in slowing tumor recurrence in glioblastoma, an aggressive and often fatal brain cancer.
Published in May in Cell Death and Disease, the study identifies a previously underappreciated feature of glioblastoma stem-like cells that creates a new therapeutic opportunity. Using advanced imaging and molecular tools, the team mapped how connexin 43, a gap junction protein, interacts with the cell’s microtubule network in these resistant cancer cells.
Glioblastoma is the most common malignant primary brain tumor and remains extremely difficult to treat. Typical care includes maximal safe surgical removal followed by radiation and chemotherapy with temozolomide, but the disease almost always returns because a subset of treatment-resistant glioblastoma stem cells survive and regenerate the tumor.
Samy Lamouille, an assistant professor at the Fralin Biomedical Research Institute and corresponding author of the study, explains that glioblastoma stem cells adapt to their environment and therapy, often entering a dormant state that allows them to survive treatment and later rebuild the tumor. Targeting this cell population is therefore critical to prevent recurrence.
The Lamouille lab focuses on how cancer cells communicate with each other and with their environment, particularly through connexin 43, a protein that forms gap junctions and mediates direct cell-to-cell signaling. Connexin 43’s role in cancer is complex: depending on its levels and location within cells, it can either suppress or promote tumor growth.
Using super-resolution microscopy—an approach that resolves protein localization at the nanoscale—researchers including Associate Professor James Smyth observed that connexin 43 in glioblastoma stem-like cells localizes along microtubules throughout the cytoplasm. Building on that observation, the team tested JM2, a peptide derived from the tubulin-binding region of connexin 43, to selectively disrupt this interaction while leaving other connexin 43 functions intact.
Rob Gourdie, who originally developed the JM2 peptide, joined the work and observed a striking response: JM2 not only prevented connexin 43 from binding microtubules but also induced selective cell death in glioblastoma stem-like cells, with healthy brain cells remaining unaffected. In three-dimensional gliosphere models, cultures visibly shrank after JM2 treatment, and this peptide alone displayed unexpected potency against tumor-forming cells.
Further testing in cell cultures and animal models confirmed that disrupting connexin 43–microtubule interactions with JM2 impaired the maintenance of glioblastoma stem-like cells and significantly slowed tumor growth in vivo. Although further research is needed to establish safety and effectiveness in humans, these preclinical results suggest that JM2 could be combined with existing chemotherapy to reduce recurrence and improve survival.
To advance the approach toward clinical use, the team is exploring targeted delivery strategies for JM2, including biodegradable nanoparticles and viral vectors designed to concentrate the peptide in glioblastoma cells and limit systemic exposure.
Note: Lamouille and Gourdie are co-founders of Acomhal Research Inc., which licensed the JM2 peptide to support development efforts aimed at translating the discovery into treatments for cancer patients.
About this glioblastoma brain cancer research news
Author:Leigh Anne Kelley
Source: Virginia Tech
Contact: Leigh Anne Kelley – Virginia Tech
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Cytoplasmic connexin43-microtubule interactions promote glioblastoma stem-like cell maintenance and tumorigenicity” by Samy Lamouille et al. Cell Death and Disease
Abstract
Cytoplasmic connexin43-microtubule interactions promote glioblastoma stem-like cell maintenance and tumorigenicity
Glioblastoma (GBM) is the most common primary tumor of the central nervous system. A major challenge in GBM treatment is the resistance to chemotherapy and radiotherapy observed in subpopulations of cancer cells, including glioblastoma stem-like cells (GSCs). These cells can self-renew and differentiate, enabling tumor recurrence after treatment.
The gap junction protein connexin 43 (Cx43) has complex roles in cancer, and prior work associated Cx43 with chemotherapy resistance in GBM. This study reports increased direct interaction between cytoplasmic, non-junctional Cx43 and microtubules in GSCs. The authors hypothesize that Cx43–microtubule complexes are essential for GSC survival and maintenance, and they set out to disrupt this interaction without impairing other Cx43 functions such as gap junction formation.
Using a Cx43-mimetic peptide derived from the carboxyl-terminal tubulin-binding domain (JM2), the researchers disrupted Cx43–microtubule interactions in GSCs. Administration of JM2 significantly reduced GSC survival in vitro and limited tumor growth from GSC-derived and patient-derived xenografts in vivo. These results identify JM2 as a novel peptide candidate to target glioblastoma stem-like cells in GBM treatment.