SCSAP SPEAKER SPOTLIGHT
Roel Verhaak, Ph.D.
Harvey and Kate Cushing Professor of Neurosurgery
Department of Neurosurgery
Yale School of Medicine
Short Bio
Roel Verhaak, PhD., is a Professor in the Department of Neurosurgery at the Yale School of Medicine. Following graduation with a Ph.D. in medicine from the Erasmus University Medical Center in Rotterdam, the Netherlands, Roel joined the Broad Institute/Dana-Farber Cancer Institute as a postdoctoral associate, supported by a fellowship from the Dutch Cancer Society. During his time at the Broad, he was part of the team analyzing data from The Cancer Genome Atlas. He led the identification and characterization of gene expression subtypes in glioblastoma, work that resulted in a seminal Cancer Cell 2010 publication.
Roel moved to MD Anderson Cancer Center in Houston, TX, in 2010 to start his own lab. Since then, the Verhaak lab has studied tumor evolution and mechanisms of therapy resistance in low- and high-grade gliomas. The group was foundational in establishing the Glioma Longitudinal Analysis Consortium, which has established a resource of molecular profiles over time on a large cohort of patients with a glioma. They identified and described genetic ‘scars’ and cellular phenotypes associated with glioma progression and disease recurrence. Extrachromosomal DNA amplifications were discovered as critical drivers and are now a major part of the team’s research. After being affiliated with the Jackson Laboratory for Genomic Medicine from 2016, the Verhaak lab joined the School of Medicine, Department of Neurosurgery, in 2023. Roel Verhaak is a recipient of the AAAS Wachtel Award, the Agilent Early Career Professor Award, and the Peter Steck Memorial Award, and is a co-founder of Boundless Bio.
Abstract
Despite standard treatment, IDH-mutant gliomas inevitably recur. Therapeutic resistance may result from a combination of intratumoral cellular heterogeneity, epigenetic evolution, and acquired genetic alterations. We charted evolution of IDH-mutant glioma through multi-platform single-nucleus and bulk characterization of longitudinally collected specimens. In addition to defining IDH-mutant malignant cellular states that were reminiscent of IDH-wild type glioma, we analyzed open chromatin accessibility data to define state-specific differentially accessible peaks which supported that the malignant states are epigenetically encoded. Between the time points of collection, we found that there was a longitudinal increase in the cycling, undifferentiated, and mesenchymal-like populations with a corresponding decrease in the astrocyte-like population. Longitudinal genetic analysis revealed that 19 of 35 tumors acquired at least one of the following genetic alterations: treatment-associated hypermutation, cell cycle alteration, or large changes in copy number alterations. Importantly, tumors that acquired these key genetic alterations demonstrated significant shifts towards reduced differentiation and increased cycling populations while those tumors that did not had more stable malignant profiles. Collectively, our results suggest a common cellular hierarchy across IDH-mutant gliomas with a shift towards reduced differentiation, increased cycling populations during disease progression that is driven by acquired genetic alterations.
Publications:
Mapping extrachromosomal DNA amplifications during cancer progression.
A brave new framework for glioma drug development.
Oncogenic composite mutations can be predicted by co-mutations and their chromosomal location.
The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.
Defining the Role of Extrachromosomal DNA Amplifications in Medulloblastoma.
Quality of life after surgery for lower grade gliomas.