The team aims to uncover how glioblastoma, the most aggressive form of brain cancer, originates from normal progenitor cells in the developing brain. New therapies could result.
A multi-institution team led by Arnold Kriegstein, MD, PhD, professor of neurology at UCSF, has been awarded a $13.5 million grant from the California Institute of Regenerative Medicine (CIRM) to decipher the origins and vulnerabilities of glioblastoma stem cells.
This research aims to uncover how glioblastoma, the most aggressive form of brain cancer, originates from normal progenitor cells in the developing brain, and how it hijacks the brain’s own electrical signals to drive its growth. By understanding these processes, the team expects to identify new therapeutic targets that stop malignant differentiation of brain stem cells or disrupt the electrical lifelines cancer cells use to survive and spread.
“This research will enable us to move beyond treating the symptoms of glioblastoma to fundamentally understanding its cellular origins and how it exploits neural circuitry to thrive,” Dr. Kriegstein said. “By mapping these mechanisms at the single-cell level, we can develop precision therapies that suppress tumor growth and prevent recurrence.”
The team comprises scientists at three leading research institutions: UCSF, Stanford, and the Salk Institute in La Jolla, CA.
At UCSF, Kriegstein, the lead principal investigator on the grant, will use CRISPR modulation to identify and target the molecular drivers that transform normal progenitor cells into cancer stem cells. Shawn Hervey-Jumper, MD, professor of neurological surgery, will provide connectivity-annotated clinical samples and use brain assembloid models to test therapeutic interventions, bringing vital medical expertise to ensure the project’s translational integration. Meanwhile, Jingjing Li, PhD, associate professor of neurology, will integrate the project’s massive multi-omics datasets into AI-driven models to predict disease trajectory, patient outcomes and new biomarkers.
At Stanford University, Michelle Monje, MD, professor of pediatric neuro-oncology, will lead investigations into cancer neuroscience to discover how tumors hijack electrical signals from neurons to drive their growth, leveraging her clinical experience treating brain tumor patients to guide the research. Li Wang, PhD, assistant professor of biology, will trace the developmental origins of these malignant cells back to specific progenitor populations. Lars Steinmetz, PhD and Michael Snyder, PhD, professors of genetics, will employ cutting-edge genomic and proteomic technologies to resolve the clonal history and protein-level transitions of individual glioblastoma cells.
At the Salk Institute, Joseph Ecker, PhD, professor of plant molecular and cellular biology, will apply specialized single-nucleus epigenomic sequencing to map the DNA methylation and 3D chromatin architecture of glioblastoma stem cells. By comparing these malignant landscapes to normal brain cells, his team aims to uncover the specific regulatory switches that are flipped during tumor initiation and progression.
The grant application was coordinated through QB3. “Our institute serves the state of California,” said QB3 Director David Schaffer, PhD, a UC Berkeley professor of chemical and biomolecular engineering. “Our collaborative research initiative brings scientists across multiple campuses and organizations together to take on audacious challenges. We thank Dr. Kriegstein for leading this impressive team. When discoveries emerge from their research, QB3 can advise scientists on how to create and build a company to advance potential therapies to the clinic.”
The grant was awarded through CIRM’s DISC4 program, which accelerates the discovery of mechanisms underlying neuropsychiatric disorders leading to the identification and validation of novel targets and biomarkers.
“Multidisciplinary research across large teams that integrates complementary approaches is required to better understand complex diseases of the central nervous system, such as glioblastoma,” said Chan Tan, PhD, senior science officer for discovery and education at CIRM. “The research team led by Arnold Kriegstein epitomizes the approach we are hoping to foster through the DISC4 program.”
The grant application was managed and co-written by QB3 Grants Coordinator Lise Barbé, PhD. DISC4 grants support expansive, cross-disciplinary studies led by large collaborative teams that apply a range of technologies and approaches. “It’s a privilege to assist our diverse team,” said Barbé, who will serve as project manager.
QB3’s Collaborative Research initiative launched in 2024; Barbé has led it from its inception. In December of that year, she successfully won funding, including a $12.3 million CIRM DISC4 grant, for a multicampus UC group exploring the genetic origins of autism. Another nascent program aims to restore tolerance in autoimmune disease. For more information about QB3 Collaborative Research, contact [email protected].