Jeff C Carlson1,2, Manuel Cantu Gutierrez1,3,4, Brittney Lozzi2, Emmet Huang-Hobbs2,5, Williamson D Turner3,4,6, Burak Tepe7, Yiqun Zhang8, Alexander M Herman3,4, Ganesh Rao9, Chad J Creighton8,10, Joshua D Wythe1,3,4,6, Benjamin Deneen1,2,9. 1. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas. 2. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas. 3. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas. 4. Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas. 5. The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas. 6. Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas. 7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. 8. Dan L Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, Texas. 9. Department of Neurosurgery, Baylor College of Medicine, Houston, Texas. 10. Department of Medicine, Baylor College of Medicine, Houston, Texas.
Abstract
BACKGROUND: Glioblastoma is the most common and aggressive type of primary brain tumor, as most patients succumb to the disease less than two years after diagnosis. Critically, studies demonstrate that glioma recruits surrounding blood vessels, while some work suggests that tumor stem cells themselves directly differentiate into endothelial cells, yet the molecular and cellular dynamics of the endothelium in glioma are poorly characterized. The goal of this study was to establish molecular and morphological benchmarks for tumor associated vessels (TAVs) and tumor derived endothelial cells (TDECs) during glioblastoma progression. METHODS: Using In-Utero Electroporation and CRISPR/Cas9 genome engineering to generate a native, immunocompetent mouse model of glioma, we characterized vascular-tumor dynamics in three dimensions during tumor progression. We employed bulk and single-cell RNA-Sequencing to elucidate the relationship between TAVs and TDECs. We confirmed our findings in a patient derived orthotopic xenograft (PDOX) model. RESULTS: Using a mouse model of glioma, we identified progressive alteration of vessel function and morphogenesis over time. We also showed in our mouse model that TDECs are a rare subpopulation that contributes to vessels within the tumor, albeit to a limited degree. Furthermore, transcriptional profiling demonstrates that both TAVs and TDECs are molecularly distinct, and both populations feature extensive molecular heterogeneity. Finally, the distinct molecular signatures of these heterogeneous populations are also present in human glioma. CONCLUSIONS: Our findings show extensive endothelial heterogeneity within the tumor and tumor microenvironment and provide insights into the diverse cellular and molecular mechanisms that drive glioma vascularization and angiogenesis during tumorigenesis.
BACKGROUND: Glioblastoma is the most common and aggressive type of primary brain tumor, as most patients succumb to the disease less than two years after diagnosis. Critically, studies demonstrate that glioma recruits surrounding blood vessels, while some work suggests that tumor stem cells themselves directly differentiate into endothelial cells, yet the molecular and cellular dynamics of the endothelium in glioma are poorly characterized. The goal of this study was to establish molecular and morphological benchmarks for tumor associated vessels (TAVs) and tumor derived endothelial cells (TDECs) during glioblastoma progression. METHODS: Using In-Utero Electroporation and CRISPR/Cas9 genome engineering to generate a native, immunocompetent mouse model of glioma, we characterized vascular-tumor dynamics in three dimensions during tumor progression. We employed bulk and single-cell RNA-Sequencing to elucidate the relationship between TAVs and TDECs. We confirmed our findings in a patient derived orthotopic xenograft (PDOX) model. RESULTS: Using a mouse model of glioma, we identified progressive alteration of vessel function and morphogenesis over time. We also showed in our mouse model that TDECs are a rare subpopulation that contributes to vessels within the tumor, albeit to a limited degree. Furthermore, transcriptional profiling demonstrates that both TAVs and TDECs are molecularly distinct, and both populations feature extensive molecular heterogeneity. Finally, the distinct molecular signatures of these heterogeneous populations are also present in human glioma. CONCLUSIONS: Our findings show extensive endothelial heterogeneity within the tumor and tumor microenvironment and provide insights into the diverse cellular and molecular mechanisms that drive glioma vascularization and angiogenesis during tumorigenesis.
Authors: Evan Z Macosko; Anindita Basu; Rahul Satija; James Nemesh; Karthik Shekhar; Melissa Goldman; Itay Tirosh; Allison R Bialas; Nolan Kamitaki; Emily M Martersteck; John J Trombetta; David A Weitz; Joshua R Sanes; Alex K Shalek; Aviv Regev; Steven A McCarroll Journal: Cell Date: 2015-05-21 Impact factor: 41.582
Authors: Jayashree Kalpathy-Cramer; Vyshak Chandra; Xiao Da; Yangming Ou; Kyrre E Emblem; Alona Muzikansky; Xuezhu Cai; Linda Douw; John G Evans; Jorg Dietrich; Andrew S Chi; Patrick Y Wen; Stephen Stufflebeam; Bruce Rosen; Dan G Duda; Rakesh K Jain; Tracy T Batchelor; Elizabeth R Gerstner Journal: J Neurooncol Date: 2016-11-16 Impact factor: 4.130
Authors: Rakesh K Jain; Emmanuelle di Tomaso; Dan G Duda; Jay S Loeffler; A Gregory Sorensen; Tracy T Batchelor Journal: Nat Rev Neurosci Date: 2007-08 Impact factor: 34.870
Authors: Chih-Wei Hsu; Juan Cerda; Jason M Kirk; Williamson D Turner; Tara L Rasmussen; Carlos P Flores Suarez; Mary E Dickinson; Joshua D Wythe Journal: Elife Date: 2022-10-11 Impact factor: 8.713