Another hurdle to the success of new brain tumor treatments is that the tissue of many brain tumors is heterogeneous and does not uniformly respond to treatment. Furthermore, brain tumors evolve when the patient undergoes treatment, ultimately leading to treatment resistance. We are leveraging emerging technologies such as single cell RNA-sequencing to profile brain tumors at single cell resolution to define tumor heterogeneity and treatment resistance mechanisms in brain tumors. We are particularly interested in exploring pediatric brain tumors, low grade gliomas, glioneuronal tumors and tumors with mutations in the BRAF oncogene in this manner.
Model for glioma differentiation hierarchies based on single cell RNA-sequencing analyses of primary human brain tumors. The schematic shows differences in abundance of cycling cells and cellular differentiation state for various subtypes of gliomas. The y-axis shows differentiation state of the tumor cells, ranging from undifferentiated neuronal progenitor-like cells at the top to more differentiated mature glia-like cells at the bottom. The x-axis shows three major glioma subytpes, including IDH-mutated oligodendrogliomas (IDH-O) and astrocytomas (IDH-A), diffuse midline gliomas with H3K27M mutation and pilocytic astrocytomas with alterations in the BRAF oncogene (BRAF-PA). The BRAF-PAs resemble a more differentiated lineage hierarchy compared to the IDH- and H3K27M-mutated tumors. These findings may underlie the differing clinical behavior and varying responses to treatment of these brain tumor subtypes.
Figure from: Reitman ZJ, Paolella BR, et al., Mitogenic and progenitor gene programmes in single pilocytic astrocytoma cells. Nat Commun. 2019 PMID: 31427603
Representative publications:
Mitogenic and progenitor gene programmes in single pilocytic astrocytoma cells. Reitman ZJ, Paolella BR, Bergthold G, Pelton K, Becker S, Jones R, Sinai CE, Malkin H, Huang Y, Grimmet L, Herbert ZT, Sun Y, Weatherbee JL, Alberta JA, Daley JF, Rozenblatt-Rosen O, Condurat AL, Qian K, Khadka P, Segal RA, Haas-Kogan D, Filbin MG, Suva ML, Regev A, Stiles CD, Kieran MW, Goumnerova L, Ligon KL, Shalek AK, Bandopadhayay P, Beroukhim R. Nat Commun. 2019 Aug 19;10(1):3731. doi: 10.1038/s41467-019-11493 PMID: 31427603
.Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population. Regal JA, Guerra García ME, Jain V, Chandramohan V, Ashley DM, Gregory SG, Thompson EM, López GY, Reitman ZJ. Acta Neuropathol Commun. 2023 Mar 25;11(1):50. doi: 10.1186/s40478-023-01548-3. PMID: 36966348.