In a recent publication from the Millman Lab titled “Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression,” Dr. Matthew Ishahak and colleagues developed engineered glioblastoma brain organoids (eGBOs) to investigate tumor progression in glioblastoma (GBM), an aggressive form of brain cancer that is highly resistant to therapy.
The study, published in Advanced Science, utilized genetic engineering technology to introduce oncogenic mutations in developing brain organoids to model early GBM progression. Single-cell and spatial transcriptomic analyses revealed that these mutations disrupt normal neurodevelopment gene regulatory networks resulting in changes in cellular composition and spatial organization. Upon transplantation into mice, the eGBOs formed tumors that resembled human GBM samples. Integrative single-cell trajectory analysis of engineered tumor cells and patient GBM samples revealed changes in developmental cell states underlying tumor progression. This work provides an important validation of engineered cancer organoids as a model of GBM tumorigenesis that can be used for future preclinical development of new therapies.
Dr. Ishahak joined the Millman Lab interested in using stem cells to generate organoids – artificially grown masses of cells that resemble organs – to build upon research from his Ph.D. He focused on recreating various organoid differentiation protocols and successfully created a brain organoid. Through a collaboration between Dr. Jeffrey Millman and Dr. Albert Kim, Director of the Brain Tumor Center at WashU Medicine, Dr. Ishahak developed a unique project based on his goal to utilize organoids for disease modeling applications. His approach enables researchers to study the disease at earlier stages of cancer than are typically attainable from patient samples since patients often arrive for treatment with advanced tumors. “This gives us a new window to view how cancer progresses early on in a very specific, mutation-focused way,” Dr. Ishahak said.
While Dr. Ishahak always had an interest in medicine and biology, his high school physics teacher encouraged him to pursue engineering, encouraging those interested in medicine to study something more applied rather than just biology to diversify their knowledge. “I didn’t just want to read about biology in textbooks. I wanted to apply that knowledge in a hands-on way. Also, I like building things.” Combining these interests, Dr. Ishahak sought to develop new disease models that could be used to improve preclinical testing of new drugs and therapies.
During his graduate training, Dr. Ishahak’s research focused on developing organs-on-chips, which combine microfluidics and tissue engineering to create miniaturized models of human physiology. His work was part of the pioneering efforts to establish organoids-on-chip and define the requirements to support 3D organoid cultures. Using isolated human pancreatic islets and the organoid microphysiological system he developed, Dr. Ishahak and his colleagues demonstrated the ability to maintain islet function in vitro and study islet health. Thinking about the next steps for this research, Dr. Ishahak said, “We have problems with human islets because of lack of availability and heterogeneity, so if you want to be able to study [islets and associated diseases], stem cells are a great solution.” So, he joined the Millman Lab post-graduation to gain experience with stem cell-derived islets.
Dr. Ishahak has been a postdoc in the Millman Lab for nearly five years and is looking forward to the next stage of his career: starting his own lab space as an independent faculty member at another university. This next phase of this research will involve using the now-validated GBM model to further investigate the mechanisms of tumor progression and identify which genes regulate this process. This will be achieved using more advanced spatial sequencing and multiomic single-cell sequencing technologies.
When asked why he decided to stay in academia rather than go on to a career in the biomedical industry, Dr. Ishahak said he worked for a big company during his undergraduate training and did not enjoy being in an office every day. Rather than do the same thing every day at a desk, he wanted to keep taking on new challenges at the cutting edge of research. While he enjoys all of the new challenges that come with academia, mentoring has long been one of the best parts of research for Dr. Ishahak and is a driver of his desire for a lab of his own. “I kind of just fell in love with [academia] as I did it. As I worked in labs and students would come in, and I would help them, the fulfillment I got from that kept me going… Kept me excited.” He particularly enjoys showing students that research is exciting and fun, nurturing their interest in science, and seeing those students go on to their own Ph.D. programs.
Outside the lab, Dr. Ishahak’s dedication to physical fitness mirrors his scientific mindset: focused, disciplined, and always striving for improvement. Whether swimming, biking, or training for a triathlon, the perseverance he cultivates through these activities fuels his work in the lab. Read more about Dr. Ishahak’s groundbreaking research on eGBOs in Advanced Science here.
M. Ishahak, R. H. Han, D. Annamalai, T. Woodiwiss, C. McCornack, R. T. Cleary, P. A. DeSouza, X. Qu, S. Dahiya, A. H. Kim, J. R. Millman, Genetically Engineered Brain Organoids Recapitulate Spatial and Developmental States of Glioblastoma Progression. Adv. Sci. 2025, 2410110. https://doi.org/10.1002/advs.202410110