Akram Hamed

All Publications

• Gliomagenesis mimics an injury response orchestrated by neural crest-like cells. Nature Hamed, A. A., Hua, K., Trinh, Q. M., Simons, B. D., Marioni, J. C., Stein, L. D., Dirks, P. B. 2025; 638 (8050): 499-509

  Abstract

  Glioblastoma is an incurable brain malignancy. By the time of clinical diagnosis, these tumours exhibit a degree of genetic and cellular heterogeneity that provides few clues to the mechanisms that initiate and drive gliomagenesis1,2. Here, to explore the early steps in gliomagenesis, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging, to initiate and then closely track tumour formation. We isolated labelled and unlabelled cells at multiple stages-before the first visible abnormality, at the time of the first visible lesion, and then through the stages of tumour growth-and subjected cells of each stage to single-cell profiling. We identify a malignant cell state with a neural crest-like gene expression signature that is highly abundant in the early stages, but relatively diminished in the late stage of tumour growth. Genomic analysis based on the presence of copy number alterations suggests that these neural crest-like states exist as part of a heterogeneous clonal hierarchy that evolves with tumour growth. By exploring the injury response in wounded normal mouse brains, we identify cells with a similar signature that emerge following injury and then disappear over time, suggesting that activation of an injury response program occurs during tumorigenesis. Indeed, our experiments reveal a non-malignant injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells. Collectively, our findings provide insight into the early stages of glioblastoma, identifying a unique cell state and an injury response program tied to early tumour formation. These findings have implications for glioblastoma therapies and raise new possibilities for early diagnosis and prevention of disease.

  View details for DOI 10.1038/s41586-024-08356-2

  View details for PubMedID 39743595

  View details for PubMedCentralID PMC11821533

• A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours. Nature communications Hamed, A. A., Kunz, D. J., El-Hamamy, I., Trinh, Q. M., Subedar, O. D., Richards, L. M., Foltz, W., Bullivant, G., Ware, M., Vladoiu, M. C., Zhang, J., Raj, A. M., Pugh, T. J., Taylor, M. D., Teichmann, S. A., Stein, L. D., Simons, B. D., Dirks, P. B. 2022; 13 (1): 4178

  Abstract

  Human cerebral cancers are known to contain cell types resembling the varying stages of neural development. However, the basis of this association remains unclear. Here, we map the development of mouse cerebrum across the developmental time-course, from embryonic day 12.5 to postnatal day 365, performing single-cell transcriptomics on >100,000 cells. By comparing this reference atlas to single-cell data from >100 glial tumours of the adult and paediatric human cerebrum, we find that tumour cells have an expression signature that overlaps with temporally restricted, embryonic radial glial precursors (RGPs) and their immediate sublineages. Further, we demonstrate that prenatal transformation of RGPs in a genetic mouse model gives rise to adult cerebral tumours that show an embryonic/juvenile RGP identity. Together, these findings implicate the acquisition of embryonic-like states in the genesis of adult glioma, providing insight into the origins of human glioma, and identifying specific developmental cell types for therapeutic targeting.

  View details for DOI 10.1038/s41467-022-31408-y

  View details for PubMedID 35853870

  View details for PubMedCentralID PMC9296666