A novel stem cell culture model of recurrent glioblastoma.
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with average disease relapse at 9 months and median survival rarely extending beyond 15 months. Brain tumor stem cells (BTSCs) have been implicated in not only initiating GBM but also conferring resistance to therapy. However, it is not clear whether the BTSC population that initiates tumor growth is also responsible for GBM recurrence. In this study, we have developed a novel in vitro treatment model to profile the evolution of primary treatment-naïve GBM BTSCs through chemoradiotherapy. We report that our in vitro model enriched for a CD15+/CD133- BTSC population, mirroring the phenotype of BTSCs in recurrent GBM. We also show that in vitro treatment increased stem cell gene expression as well as self-renewal capacity of primary GBMs. In addition, the chemoradiotherapy-refractory gene signature obtained from gene expression profiling identified a hyper-aggressive subtype of glioma. The delivery of in vitro chemoradiotherapy to primary GBM BTSCs models several aspects of recurrent GBM biology, and could be used as a discovery and drug-screening platform to uncover new biological drivers and therapeutic targets in GBM.
McMaster Stem Cell and Cancer Research Institute, McMaster University, MDCL 5027, 1200 Main Street West, Hamilton, ON, L8S 4K1, Canada.|Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Maleeha A
MA
Qazi
McMaster Stem Cell and Cancer Research Institute, McMaster University, MDCL 5027, 1200 Main Street West, Hamilton, ON, L8S 4K1, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Parvez
P
Vora
McMaster Stem Cell and Cancer Research Institute, McMaster University, MDCL 5027, 1200 Main Street West, Hamilton, ON, L8S 4K1, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Chitra
C
Venugopal
McMaster Stem Cell and Cancer Research Institute, McMaster University, MDCL 5027, 1200 Main Street West, Hamilton, ON, L8S 4K1, Canada.|Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Nicole
N
McFarlane
McMaster Stem Cell and Cancer Research Institute, McMaster University, MDCL 5027, 1200 Main Street West, Hamilton, ON, L8S 4K1, Canada.|Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Minomi K
MK
Subapanditha
Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
Naresh K
NK
Murty
Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.|McMaster Centre for Functional Genomics, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
John A
JA
Hassell
Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.|McMaster Centre for Functional Genomics, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
Robin M
RM
Hallett
McMaster Stem Cell and Cancer Research Institute, McMaster University, MDCL 5027, 1200 Main Street West, Hamilton, ON, L8S 4K1, Canada. ssingh@mcmaster.ca.|Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. ssingh@mcmaster.ca.|Department of Surgery, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada. ssingh@mcmaster.ca.
Sheila K
SK
Singh
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015703:Antigens, CD / Q000378:metabolism; D000969:Antinematodal Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology*; D000066673:Cell Self Renewal / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000969:Antinematodal Agents; D000970:Antineoplastic Agents; C069077:BMI1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D063150:Polycomb Repressive Complex 1