Next Article in Journal
Chimeric Antigen Receptor T Cell Therapy for Solid Tumors: Current Status, Obstacles and Future Strategies
Next Article in Special Issue
CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1
Previous Article in Journal
Tumor-Associated Macrophages Induce Endocrine Therapy Resistance in ER+ Breast Cancer Cells
Previous Article in Special Issue
Virus-Based Immunotherapy of Glioblastoma
Article Menu
Issue 2 (February) cover image

Export Article

Open AccessArticle
Cancers 2019, 11(2), 190; https://doi.org/10.3390/cancers11020190

Intratumoural Heterogeneity Underlies Distinct Therapy Responses and Treatment Resistance in Glioblastoma

1
Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia
2
School of Medicine, Griffith University, Gold Coast 4215, QLD, Australia
3
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia
4
Department of Neurosurgery, Royal Brisbane and Women’s Hospital, Brisbane 4006, QLD, Australia
5
School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane 4059, QLD, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Co-senior authors.
Received: 24 December 2018 / Revised: 25 January 2019 / Accepted: 2 February 2019 / Published: 6 February 2019
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
  |  
PDF [4768 KB, uploaded 18 February 2019]
  |  

Abstract

Glioblastomas are the most common and lethal neoplasms of the central nervous system. Neighbouring glioma cells maintain extreme degrees of genetic and phenotypic variation that form intratumoural heterogeneity. This genetic diversity allows the most adaptive tumour clones to develop treatment resistance, ultimately leading to disease recurrence. We aimed to model this phenomenon and test the effectiveness of several targeted therapeutic interventions to overcome therapy resistance. Heterogeneous tumour masses were first deconstructed into single tumour cells, which were expanded independently as single-cell clones. Single nucleotide polymorphism arrays, whole-genome and RNA sequencing, and CpG methylation analysis validated the unique molecular profile of each tumour clone, which displayed distinct pathologic features, including cell morphology, growth rate, and resistance to temozolomide and ionizing radiation. We also identified variable sensitivities to AURK, CDK, and EGFR inhibitors which were consistent with the heterogeneous molecular alterations that each clone harboured. These targeted therapies effectively eliminated the temozolomide- and/or irradiation-resistant clones and also parental polyclonal cells. Our findings indicate that polyclonal tumours create a dynamic environment that consists of diverse tumour elements and treatment responses. Designing targeted therapies based on a range of molecular profiles can be a more effective strategy to eradicate treatment resistance, recurrence, and metastasis. View Full-Text
Keywords: glioblastoma; intratumoural heterogeneity; tumour resistance; personalised therapy; targeted therapy; combination therapy; drug screens glioblastoma; intratumoural heterogeneity; tumour resistance; personalised therapy; targeted therapy; combination therapy; drug screens
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Akgül, S.; Patch, A.-M.; D’Souza, R.C.; Mukhopadhyay, P.; Nones, K.; Kempe, S.; Kazakoff, S.H.; Jeffree, R.L.; Stringer, B.W.; Pearson, J.V.; Waddell, N.; Day, B.W. Intratumoural Heterogeneity Underlies Distinct Therapy Responses and Treatment Resistance in Glioblastoma. Cancers 2019, 11, 190.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top