title: Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition.
abstract: Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuum of multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Clinical Chemistry and Pharmacology, Uppsala University Hospital, 751 85 Uppsala, Sweden. Electronic address: anna.segerman@igp.uu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Segerman
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Niklasson
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Haglund
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bergström
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Jarvius
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Westermark
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Demet
authors.initials: D
authors.lastname: Sönmez
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Hermansson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Kastemar
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Naimaie-Ali
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Frida
authors.initials: F
authors.lastname: Nyberg
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Berglund
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Sundström
authors.affiliation: Department of Neurosurgery, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Hesselager
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Gustafsson
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; National Veterinary Institute, 750 07 Uppsala, Sweden. Electronic address: bo.segerman@igp.uu.se.
authors.forename: Bo
authors.initials: B
authors.lastname: Segerman
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden. Electronic address: bengt.westermark@igp.uu.se.
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic
chemical_list: D009363:Neoplasm Proteins
keywords: clones; drug; glioma; heterogeneity; intratumoral; mesenchymal; proneural; radiation; resistant; transition