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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01119

Tissues harvested using an automated surgical approach confirm molecular heterogeneity of glioblastoma and enhance specimen’s translational research value

Edie Zusman1,  Maxim Sidorov2,  Alexandria Ayala3,  Jimmin Chang4, Eric Singer2, Michelle Chen2, Pierre Desprez2, Sean McAllister2,  Nathan Salomonis5,  Kashish Chetal6, Gautam Prasad3, Tyler Kang3,  Joseph Mark7,  Lawrence Dickinson3 and  Liliana Soroceanu2*
  • 1NorthBay Healthcare, United States
  • 2California Pacific Medical Center, United States
  • 3Eden Medical Center, Sutter Health, United States
  • 4Sutter Institute for Medical Research, United States
  • 5Cincinnati Children Hospital Medical Center, United States
  • 6Cincinnati Children's Hospital Medical Center, United States
  • 7Nico Corporation, United States

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Designing effective individualized therapies for GBM requires quality fresh tissue specimens, and a comprehensive molecular profile of this highly heterogenous neoplasm. Novel neuro-surgical approaches, such as the automated resection NICO Myriad™ system, are increasingly used by neurosurgeons to better reach the invasive front of tumors. However, no information exists on how harvesting GBM tissue using this approach may impact the translational research value of the sample. Here, we set out to characterize matched specimens from fifteen patients, where one tissue sample was obtained using traditional tumor de-bulking (herein referred to as “en bloc” sample), and the other sample was obtained using the MyriadTM System (herein referred to as “Myriad” sample). We investigated the fidelity of patient derived xenografts (PDX) for each sample type to the corresponding human tissues and evaluated the added value of sequencing both samples for each patient. Matched en bloc and Myriad samples processed in parallel, were subjected to the following assays: cell viability, self-renewal, in vivo tumorigenicity using an orthotopic model of glioma, genomic sequencing, and pharmacological testing using PI3K-MTOR pathway inhibitors. Our results demonstrate that primary GBM cultures derived from matched specimens grew at similar rates (correlation coefficient R=0.72), generated equivalent number of neurospheres, and had equivalent tumorigenic potential in vivo (mouse survival correlation coefficient R=0.93). DNA Sequencing using the Illumina tumor panel amplicons revealed over 70% concordance in non-synonymous mutations between matched human GBM specimens. PDX genomic profiles were also highly concordant with the corresponding patient tissues (>70%). RNA sequencing of paired GBM samples revealed unique genomic variants and differential gene expression between the en bloc and Myriad specimens, with the former molecularly resembling the “tumor core” and the latter resembling the “invasive tumor front” signature. Functionally, we show that primary-derived GBM cells -obtained after fresh specimen’s dissociation- are more effectively growth-inhibited by co-targeting non-overlapping mutations enriched in each sample type, suggesting that profiling both specimens more adequately capture the molecular heterogeneity of GBM and may enhance the design accuracy and efficacy of individualized therapies.

Keywords: Glioblastoma, PDX, tumor heterogeneity, Myriad, RNA sequencing

Received: 24 Aug 2019; Accepted: 08 Oct 2019.

Copyright: © 2019 Zusman, Sidorov, Ayala, Chang, Singer, Chen, Desprez, McAllister, Salomonis, Chetal, Prasad, Kang, Mark, Dickinson and Soroceanu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Liliana Soroceanu, California Pacific Medical Center, San Francisco, California, United States, sorocel@cpmcri.org