Published on Wed Jul 07 2021

Re-convolving the compositional landscape of primary and recurrent glioblastoma using single nucleus RNA sequencing

Al-Dalahmah, O., Argenziano, M., Boyett, D., Save, A., Mahajan, A., Khan, F., Tuddenham, J., goldberg, a. r., Dovas, A., Banu, M., Furnari, J., Sudhakar, T., Bush, E., Lassman, A., Bruce, J., Sims, P., Menon, V., Canoll, P.

Glioblastoma is an aggressive diffusely infiltrating neoplasm. It spreads beyond surgical resection margins, where it intermingles with non-neoplastic brain cells. Understanding the cellular and molecular features of the glioma margin is therapeutically and prognostically important.

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Abstract

Glioblastoma is an aggressive diffusely infiltrating neoplasm that spreads beyond surgical resection margins, where it intermingles with non-neoplastic brain cells. This complex tissue harboring infiltrating glioma and non-neoplastic brain cells is the origin of tumor recurrence. Thus, understanding the cellular and molecular features of the glioma margin is therapeutically and prognostically important. Here, we used single-nucleus RNA sequencing (snRNAseq) of primary and recurrent glioma to define compositional tissue-states that correlate with radiographic and histopathologic features. We found that glioma cells can be clustered into proliferative, astrocyte-like/mesenchymal, and progenitor-like/proneural states in both the primary and post-treatment recurrence settings. We focused on non-neoplastic microenvironment cells including oligodendrocytes, myeloid cells, neurons, and astrocytes - the latter two are under-represented in single-cell RNAseq studies. Cell type-specific signatures of the astrocyte-like/mesenchymal glioma, and a subpopulation of non-neoplastic astrocytes correlated with poor prognosis, the latter correlated with glioma recurrence. Notably, astrocytes were enriched for metabolic and neurodegenerative gene signatures. Leveraging snRNAseq-derived compositional information, we define three tissue-states that correlate with radiographic localization of primary and recurrent glioma. Our findings define a compositional approach to the glioma microenvironment and reveal prognostically and anatomically relevant features paving the way to new mechanistic and therapeutic discoveries.