TY - JOUR
T1 - Functional characterization of brain tumor-initiating cells and establishment of GBM preclinical models that incorporate heterogeneity, therapy, and sex differences
AU - Garcia, Cesar A.
AU - Bhargav, Adip G.
AU - Brooks, Mieu
AU - Suarez-Meade, Paola
AU - Mondal, Sujan K.
AU - Zarco, Natanael
AU - ReFaey, Karim
AU - Jentoft, Mark
AU - Middlebrooks, Erik H.
AU - Snuderl, Matija
AU - Carrano, Anna
AU - Guerrero-Cazares, Hugo
AU - Schiapparelli, Paula
AU - Sarabia-Estrada, Rachel
AU - Quiñones-Hinojosa, Alfredo
N1 - Funding Information:
C.A. Garcia reports grants from NCI, NIH, Howard Hughes Medical Institute (HHMI), Mayo Clinic, NIH, and Eagle’s 5th District Cancer Telethon Award during the conduct of the study. A.G. Bhargav reports grants from Howard Hughes Medical Institute during the conduct of the study. E.H. Middlebrooks reports personal fees from Boston Scientific Corp. and grants and personal fees from Varian Medical Systems Inc outside the submitted work. M. Snuderl reports personal fees from Illumina, Inc., outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
A. Quiñones-Hinojosa was supported by the Mayo Clinic Professorship, a Clinician Investigator award, the Florida Department of Health Cancer Research Chair Fund, and the NIH (R43CA221490, R01CA200399, R01CA195503, and R01CA216855). C.A. Garcia was supported by the NIH and NCI Diversity Supplement Program (R01CA195503–04S1). A.G. Bhargav was supported by the Howard Hughes Medical Institute (HHMI) Medical Research Fellows Program. R. Sarabia-Estrada was supported by the Mayo Clinic Convergence Pilot Award. AC was supported by the Eagles 5th District Cancer Telethon Award. H. Guerrero-Cazares, A. Carrano, and N. Zarco were supported by the NIH (R03NS109444, K01NS110930). The authors would like to thank Dr. Steven S. Rosenfeld, Rita West, and Amanda Luu for assistance in conducting cell line kinetic growth experiments and Brandy Edenfield for assistance with murine histology staining.
Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/12
Y1 - 2021/12
N2 - Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.
AB - Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.
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U2 - 10.1158/1535-7163.MCT-20-0547
DO - 10.1158/1535-7163.MCT-20-0547
M3 - Article
C2 - 34465594
AN - SCOPUS:85120704640
VL - 20
SP - 2585
EP - 2597
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 12
ER -