Therapeutic reversal of prenatal pontine ID1 signaling in DIPG
Viveka Yadav,Micah Harris,Messinger D,Chase Thomas,Cummings,Tao Yang,Rinette Woo,Robert Siddaway,Burkert M,Stefanie Stallard,Tingting Qin,Brendan Mullan,Ruby Siada,Ramya Ravindran,Michael Niculcea,Kevin Ginn,Melissa Gener,Kathleen Dorris,Nicholas A Vitanza,Susanne V. Schmidt,Jasper Spitzer,Jiang Li,Mariella G. Filbin,Xuhong Cao,Maria G. Castro,Pedro R. Lowenstein,Rajen Mody,Chinnaiyan A,Pierre-Yves Desprez,Sandra S. McAllister,Cynthia Hawkins,Sebastian M. Waszak,Sriram Venneti,Carl Koschmann +33 more
TLDR
In this article, the authors developed an in- utero electroporation (IUE) murine H3K27M-driven tumor model, which demonstrates increased ID1 expression in H3k27m-and ACVR1-mutated tumor cells.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 tumor’s 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 Summary The transcription factor ID1 is upregulated in a subset of DIPG tumor cells, and ID1-driven invasiveness is therapeutically targetable with CBD.read more
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Therapeutic targeting of differentiation state-dependent metabolic vulnerabilities in DIPG
Nneka E. Mbah,Amy L. Myers,Chan-Goo Chung,Joyce K. Thompson,Hanna S. Hong,Peter Sajjakulnukit,Zeribe C. Nwosu,Mengrou Shan,Stefan R. Sweha,Daniella Maydan,Brandon Chen,Li Zhang,Brian Magnuson,Zirui Zui,Daniel R. Wahl,Luigi Franchi,Sameer Agnihotri,Carl Koschmann,Sriram Venneti,Costas A. Lyssiotis +19 more
TL;DR: It is shown that the AC-like cells exhibited a more mesenchymal phenotype and were thus sensitized to ferroptotic cell death and therefore more sensitive to statins and OXPHOS inhibitors.
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