Yahaya A. YABO

scRNA-seq reveals phenotypic heterogeneity and transcriptomic adaptation upon treatment in Glioblastoma
Glioblastomas are heterogeneous and aggressive type of brain tumor, which hampers patient stratification and development of effective therapies. Glioblastomas create a dynamic ecosystem, where heterogeneous tumor cells interact with the tumor microenvironment (TME) to establish different niches. Upon tumor growth, Glioblastoma cells manifest remarkable plasticity and respond flexibly to selective pressures by transiting towards states favorable to the new TME. How this phenotypic plasticity contributes to treatment resistance is currently less clear. The exact nature of treatment resistant, tolerant and sensitive glioblastoma cells remain unresolved. To investigate long-term phenotypic changes upon treatment at the single cell level we performed single cell RNA-seq (scRNA-seq) on longitudinal patient-derived xenograft (PDOX) models derived from Glioblastoma patient tumors prior and after the standard-of-care treatment. We applied advanced computational algorithms, including reference-free deconvolution methods to identify treatment resistance signatures and master regulators of the identified treatment-resistant subpopulations. scRNA-seq profiling of PDOXs treated with temozolomide revealed short-term transcriptomic changes both in tumor cells and in the mouse-derived TME. In addition, we show that PDOX models recapitulate all the major cell types and transcriptional programs reported in Glioblastoma patient samples, providing clinically relevant models for investigating treatment resistance signatures of tumor cells and associated TME. Analysis of treatment naïve and treated Glioblastomas at the single cell level revealed transcriptomic adaptation of tumor cell subpopulations towards resistant states. Certain transcriptomic changes are preserved long term, regardless of the lack of genetic evolution of the tumor cells. Phenotypic plasticity is an important factor contributing to resistance mechanisms in Glioblastoma. Key molecular regulators of tumor cell plasticity towards treatment resistance states represent novel targets for combinatorial therapies.

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