Intratumoural heterogeneity underlies distinct therapy responses and treatment resistance in glioblastoma

Seçkin Akgül, Ann Marie Patch, Rochelle C.J. D’souza, Pamela Mukhopadhyay, Katia Nones, Sarah Kempe, Stephen H. Kazakoff, Rosalind L. Jeffree, Brett W. Stringer, John V. Pearson, Nicola Waddell, Bryan W. Day

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Article number190
Number of pages17
JournalCancers
Volume11
Issue number2
DOIs
Publication statusPublished - 6 Feb 2019
Externally publishedYes

Bibliographical note

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license

Keywords

  • Combination therapy
  • Drug screens
  • Glioblastoma
  • Intratumoural heterogeneity
  • Personalised therapy
  • Targeted therapy
  • Tumour resistance

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    Akgül, S., Patch, A. M., D’souza, R. C. J., Mukhopadhyay, P., Nones, K., Kempe, S., Kazakoff, S. H., Jeffree, R. L., Stringer, B. W., Pearson, J. V., Waddell, N., & Day, B. W. (2019). Intratumoural heterogeneity underlies distinct therapy responses and treatment resistance in glioblastoma. Cancers, 11(2), [190]. https://doi.org/10.3390/cancers11020190