Transcriptomic Analysis of Image-Localized High-Grade Glioma Biopsies Reveals Meaningful Cellular States

Lee Curtin

Mayo Clinic

"Transcriptomic Analysis of Image-Localized High-Grade Glioma Biopsies Reveals Meaningful Cellular States"

High-grade glioma continues to have dismal survival with current standard-of-care treatment, owing in part to its intra- and inter-patient heterogeneity. Typical diagnostic clinical biopsies are taken from the dense tumor core to determine the presence of abnormal cells and the status of a few key genes. However, the tumor core is removed during surgery, leaving behind possibly genetically, transcriptomically and/or phenotypically distinct invasive margins that repopulate the disease. As these remaining populations are the ones ultimately being treated, it is important to know their compositional differences from the tumor core. We aim to identify the phenotypic niches defined by the relative composition of key cellular populations and understand their variation amongst patients. We have established an image-localized research biopsy study, that samples from both the invasive margin and tumor core. From this protocol, we currently have 202 samples from 58 patients with available bulk RNA-Seq, collected between Mayo Clinic and Barrow Neurological Institute. Using a single-cell reference dataset from our collaborators at Columbia University, we used CIBERSORTx, a support vector machine deconvolution method, to predict relative abundances of normal, glioma, and immune cell states for each sample. We also applied Monocle, an algorithm that uses reversed graph embedding, to this dataset. Monocle orders samples on a low dimensional space by pseudotime, and provides a graph of transitions between end states. We find that these cell state abundances connect to patient survival and show regional differences. We analyze the robustness of these methods, and highlight the importance of characterizing residual glioma to better understand the recurrent disease.
Additional authors: Sebastian Velez, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Kamila Bond, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Andrea Hawkins-Daarud, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Javier C. Urcuyo, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Gustavo De Leon, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Jazlynn Langworthy, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Christopher Sereduk, Department of Biology, Mayo Clinic, Phoenix, AZ, USA; Kyle W. Singleton, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Pamela R. Jackson, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Chandan Krishna, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA, Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; Richard S. Zimmerman, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Devi P. Patra, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Bernard R. Bendok, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA; Kris A. Smith, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA; Peter Nakaji, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA; Kliment Donev, Department of Pathology, Mayo Clinic, Phoenix, AZ, USA; Leslie C. Baxter, Department of Neurophysiology, Mayo Clinic, Phoenix, AZ, USA; Maciej M. Mrugala, Department of Neurology, Mayo Clinic, Phoenix, AZ, USA; Osama Al-Dalahmah, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA, Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; Leland S. Hu, Department of Radiology, Mayo Clinic, Phoenix, AZ, USA; Nhan L. Tran, Department of Biology, Mayo Clinic, Phoenix; Peter Canoll, Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; Kristin R. Swanson, Mathematical Neuro-Oncology Lab, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA, Department of Neurosurgery, Mayo Clinic, Phoenix, AZ, USA

---