Summary: Researchers have identified an oncogene that appears to drive glioblastoma, the most aggressive and lethal form of brain cancer. The gene, AVIL, normally helps cells regulate shape and structure, but when overactive it promotes tumor growth and spread. In laboratory mice, blocking AVIL eradicated glioblastoma cells while leaving healthy cells unharmed, pointing to a promising new therapeutic target.
Source: University of Virginia
New oncogene discovery points to an actionable target for glioblastoma treatment
Scientists at the University of Virginia report the discovery of a cancer-causing gene, AVIL, that plays a central role in glioblastoma development and progression. Because glioblastoma remains one of the deadliest cancers with limited effective therapies, the finding provides a potential route toward targeted treatment strategies aimed at a clear molecular vulnerability.
AVIL is a cytoskeleton regulator that, under normal conditions, helps cells maintain their shape and structural integrity. The research team found that when AVIL becomes overexpressed or deregulated, it fuels tumor cell proliferation, migration, and survival. Importantly, experimental silencing of AVIL eliminated glioblastoma cells in culture and halted tumor growth in mouse xenograft models while sparing normal cells and tissues. These results suggest that therapies designed to inhibit AVIL could be selective against tumor cells and have limited toxicity to healthy brain tissue.
Targeting glioblastoma through AVIL
Oncogenes are genes that, when mutated or overactive, drive cancer. The UVA team demonstrated that AVIL is consistently overexpressed across the glioblastoma samples they examined, including glioblastoma stem or initiating cells, which are thought to fuel tumor recurrence and resistance to therapy. Patients whose tumors show high AVIL expression tended to have poorer outcomes, reinforcing the clinical relevance of the finding.
Experimental evidence strengthens AVIL’s role as a bona fide oncogene. Suppressing AVIL expression in glioblastoma cells caused widespread cell death and dramatically reduced tumor formation in animal models. Conversely, increasing AVIL levels promoted cell division and movement, allowed immortalized astrocytes and fibroblasts to bypass normal growth controls, and induced features of cellular transformation. These functional assays, together with clinical correlations, support AVIL as a central driver of glioblastoma biology.
How AVIL promotes tumorigenesis
Mechanistic studies indicate AVIL exerts its tumorigenic effects in part by regulating the actin cytoskeleton—particularly filamentous actin (F-actin)—which is critical for cell shape, motility, and division. The researchers also identified a signaling axis involving the transcription factor FOXM1 and the RNA-binding protein LIN28B that links AVIL to pathways known to control proliferation and stemness. Mutations in AVIL that disrupt F-actin binding impair its ability to drive tumorigenesis, highlighting the importance of cytoskeletal regulation in its oncogenic function.
From pediatric clues to adult cancer insight
Interestingly, the discovery of AVIL’s role in glioblastoma grew out of studies on a rare pediatric cancer, rhabdomyosarcoma. Pediatric tumors often carry fewer mutations, making it easier to detect meaningful genetic alterations. While investigating a structural variant in AVIL in that context, researchers traced the gene’s abnormal activity into adult cancers and ultimately pinpointed its critical role in glioblastoma. The authors propose that similar cross-disease approaches may help uncover other previously overlooked oncogenes in adult cancers.
Publication, authorship and funding
The full study, presenting functional and mechanistic evidence for AVIL as an oncogene in glioblastoma, was published in Nature Communications. The research team includes Zhongqiu Xie, Pawel Janczyk, Ying Zhang, Aiqun Liu, Xinrui Shi, Sandeep Singh, Loryn Facemire, Kristopher Kubow, Zi Li, Yuemeng Jia, Dorothy Schafer, James W. Mandell, Roger Abounader and Hui Li.
Funding for the work came from the U.S. National Institutes of Health’s National Cancer Institute (grant CA240601) and Stand Up To Cancer (grant SU2C-AACR-IRG0409).
About this research and clinical implications
Glioblastoma remains highly lethal and resistant to conventional therapies. Current standards, including radiation combined with temozolomide chemotherapy, have provided only modest survival benefits. The identification of AVIL as a tumor-essential oncogene opens the possibility of developing targeted therapies that exploit the tumor’s dependence on this gene. Because AVIL is minimally expressed in normal brain cells but highly active in glioblastoma and its stem-like cells, AVIL-directed therapies have the potential to be both effective and selective.
The investigators emphasize that while these findings are encouraging, further preclinical development and clinical testing will be necessary to translate AVIL inhibition into a safe and effective therapy for patients. Nonetheless, the study provides a clear molecular target and a roadmap for future drug development efforts aimed at improving outcomes for people with glioblastoma.
Original research citation
Original Research (open access): “A cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma” by Zhongqiu Xie, Pawel Ł. Janczyk, Ying Zhang, Aiqun Liu, Xinrui Shi, Sandeep Singh, Loryn Facemire, Kristopher Kubow, Zi Li, Yuemeng Jia, Dorothy Schafer, James W. Mandell, Roger Abounader & Hui Li. Nature Communications.
Abstract
A cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma
Glioblastoma is a deadly cancer with few effective therapeutic options, making the identification of selective targets a high priority. The study reports that advillin (AVIL) is overexpressed across tested glioblastoma samples, including glioblastoma stem/initiating cells, while being minimally detectable in non-neoplastic astrocytes, neural stem cells, or normal brain tissue. Higher AVIL expression correlates with poorer patient prognosis. Silencing AVIL nearly eliminated glioblastoma cells in culture and profoundly inhibited tumor growth in mouse xenograft models, with no observable effect on normal control cells. Conversely, AVIL overexpression promoted cell proliferation, migration, loss of contact inhibition, and transformation of immortalized astrocytes. Mechanistically, AVIL influences tumorigenesis in part through FOXM1 and LIN28B and regulates the cytoskeleton via F-actin modulation; mutants that disrupt F-actin binding lose tumorigenic activity.