Therapeutic reversal of prenatal pontine ID1 signaling in DIPG

Yadav, V. N.; Harris, M. K.; Messinger, D.; Thomas, C.; Cummings, J. R.; Yang, T.; Woo, R.; Siddaway, R.; Burkert, M.; Stallard, S.; Qin, T.; Mullan, B.; Siada, R.; Ravindran, R.; Niculcea, M.; Ginn, K.; Gener, M. A. H.; Dorris, K.; Vitanza, N. A.; Schmidt, S.; Spitzer, J.; Jiang, L.; Filbin, M.; Cao, X.; Castro, M.; Lowenstein, P.; Mody, R.; Chinnaiyan, A.; Desprez, P.-Y.; McAllister, S.; Hawkins, C.; Waszak, S.; Venneti, S.; Koschmann, C.

doi:10.1101/2021.05.10.443452

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bioRxiv · 10.1101/2021.05.10.443452

Therapeutic reversal of prenatal pontine ID1 signaling in DIPG

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Abstract

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive brain tumor with rare survival beyond two years. This poor prognosis is largely due to the tumors highly infiltrative and invasive nature. Previous reports demonstrate upregulation of the transcription factor ID1 with H3K27M and ACVR1 mutations, but this has not been confirmed in human tumors or therapeutically targeted. We developed an in utero electroporation (IUE) murine H3K27M-driven tumor model, which demonstrates increased ID1 expression in H3K27M- and ACVR1-mutated tumor cells. In human tumors, elevated ID1 expression is associated with H3K27M/ACVR1-mutation, brainstem location, and reduced survival. The ID1 promoter demonstrates a similar active epigenetic state in H3K27M tumor cells and murine prenatal hindbrain cells. In the developing human brain, ID1 is expressed highest in oligo/astrocyte-precursor cells (OAPCs). These ID1+/SPARCL1+ cells share a transcriptional program with astrocyte-like (AC-like) DIPG cells, and demonstrate upregulation of gene sets involved with regulation of cell migration. Both genetic and pharmacologic [cannabidiol (CBD)] suppression of ID1 results in decreased DIPG cell invasion/migration in vitro and invasion/tumor growth in multiple in vivo models. CBD reduces proliferation through reactive oxygen species (ROS) production at low micromolar concentrations, which we found to be achievable in the murine brainstem. Further, pediatric high-grade glioma patients treated off-trial with CBD (n=15) demonstrate tumor ID1 reduction and improved overall survival compared to historical controls. Our study identifies that ID1 is upregulated in DIPG through reactivation of a developmental OAPC transcriptional state, and ID1-driven invasiveness of DIPG is therapeutically targetable with CBD. One Sentence SummaryThe transcription factor ID1 is upregulated in a subset of DIPG tumor cells, and ID1-driven invasiveness is therapeutically targetable with CBD.

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Yadav, V. N., Harris, M. K., Messinger, D., Thomas, C., Cummings, J. R., Yang, T., Woo, R., Siddaway, R., Burkert, M., Stallard, S., Qin, T., Mullan, B., Siada, R., Ravindran, R., Niculcea, M., Ginn, K., Gener, M. A. H., Dorris, K., Vitanza, N. A., Schmidt, S., Spitzer, J., Jiang, L., Filbin, M., Cao, X., Castro, M., Lowenstein, P., Mody, R., Chinnaiyan, A., Desprez, P.-Y., McAllister, S., Hawkins, C., Waszak, S., Venneti, S., Koschmann, C.. 2021-05-11. Therapeutic reversal of prenatal pontine ID1 signaling in DIPG. https://doi.org/10.1101/2021.05.10.443452

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