Molecular mechanisms underlying phenotypic plasticity in malignant glioma


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Costanza Lo Cascio1,Ernesto Luna1,Rohit Khurana1,Roberto Fiorelli1,Shwetal Mehta1
1Barrow Neurological Institute

Abstract

Background

Glioblastoma (GBM) is characterized by rapidly proliferating and invasive cells that infiltrate normal brain regions. Following exposure to aggressive treatment regimens, GBMs frequently shift their biological features upon recurrence, acquiring a more resistant phenotype. However, the dynamics and molecular mechanisms that facilitate GBM recurrence are still poorly understood. Considering the unchanged dismal prognosis for GBM patients, there is a need to understand, at a systems level, how plastic processes (molecular switches) in glioma stem-like cells (GSCs) may drive tumor maintenance and cancer cell adaptability in GBM. The objective our study was to determine how GSCs temporally adjust their expression profile and phenotype in response to ionizing radiation in vitro and in vivo using patient-derived xenograft (PDX) models of GBM.

Method

We established PDX GBM models by intracranially implanting two patient-derived GSC lines belonging to different GBM molecular subgroups into immunocompromised mice. The tumor-bearing mice were treated with single doses of ionizing radiation to assess acute responses to treatment. Mice from each cohort were be sacrificed at multiple distinct time points following treatment. Using immunohistochemical methods, we assessed changes in the expression of GBM subclass markers, stemness and differentiation markers, and DNA damage/repair proteins across the entire tumor population over time. To understand how GSCs respond to radiation at a molecular level, we employed mass cytometry (CyTOF) and RNA-seq to determine how important cellular signaling pathways and transcriptional programs necessary for GSC self-renewal, invasion and growth are altered at various time points post-treatment.

Results

We demonstrate that GSCs, both in vitro and in vivo, undergo an immediate response following exposure to radiation that results in a global modulation of the expression of key stemness and proliferation genes under adverse conditions.

Conclusion

Our results suggest that this acute response allows GSCs to enter a transient semi-differentiated state that favors GSC adaptability and resistance to therapy