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Molecular features unique to glioblastoma radiation resistant residual cells may affect patient outcome - a short report

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Abstract

Purpose

Previously we have shown, using a primary glioblastoma (GBM) cell model, that a subpopulation of innately radiation resistant (RR) GBM cells survive radiotherapy and form multinucleated and giant cells (MNGCs) by homotypic fusions. We also showed that MNGCs may cause relapse. Here, we set out to explore whether molecular characteristics of RR cells captured from patient-derived primary GBM cultures bear clinical relevance.

Methods

Primary cultures were derived from 19 naive GBM tumor samples. RR cells generated from these cultures were characterized using various cell biological assays. We also collected clinicopathological data of the 19 patients and assessed associations with RR variables using Spearman’s correlation test and with patient survival using Kaplan-Meier analysis. Significance was determined using a log-rank test.

Results

We found that SF2 (surviving fraction 2) values (p = 0.029), days of RR cell formation (p = 0.019) and percentage of giant cells (p = 0.034) in the RR population independently correlated with a poor patient survival. We also found that low ATM (Ataxia-telangiectasia mutated) expression levels in RR cells showed a significant (p = 0.002) negative correlation with SF2 values. A low ATM expression level in RR cells along with a high tumor volume was also found to negatively correlate with patient survival (p = 0.011). Finally, we found that the ATM expression levels in RR cells independently correlated with a poor patient survival (p = 0.014).

Conclusions

Our data indicate that molecular features of innately radiation resistant GBM cells independently correlate with clinical outcome. Our study also highlights the relevance of using patient-derived primary GBM cultures for the characterization of RR cells that are otherwise inaccessible for analysis.

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Fig. 1: Molecular features used in this study.
Fig. 2: ATM protein levels and its signaling in GBM tissues and primary cultures, and correlation analyses of molecular parameters among each other.
Fig. 3: Univariate analyses of the individual molecular and radio-pathological features on overall survival.

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Acknowledgements

We are grateful to Dr. Sadhana Kannan for help with statistical analysis and to Prof. B. J. Rao, TIFR, for providing the anti-ATM antibody. AG acknowledges DST-SERB, India for providing a National Post-Doctoral Fellowship (PDF/2016/00158), and SS acknowledges CSIR for providing a fellowship.

Funding

This study is supported by a Department of Biotechnology grant (BT/PR4020/MED/30/792/2012) to SD.

Author information

Author notes

  1. Ekjot Kaur and Jayant S. Goda contributed equally to this work.

Authors and Affiliations

  1. Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India

    Ekjot Kaur, Atanu Ghorai, Sameer Salunkhe & Shilpee Dutt

  2. Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400085, India

    Ekjot Kaur, Jayant S. Goda, Atanu Ghorai, Sameer Salunkhe, Prakash Shetty, Aliasgar V. Moiyadi, Epari Sridhar, Abhishek Mahajan, Rakesh Jalali & Shilpee Dutt

  3. Clinical Biology Lab, Department of Radiation Oncology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India

    Jayant S. Goda, Abhishek Mahajan & Rakesh Jalali

  4. Department of Neurosurgery, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India

    Prakash Shetty & Aliasgar V. Moiyadi

  5. Department of Pathology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India

    Epari Sridhar

Authors
  1. Ekjot Kaur
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  10. Shilpee Dutt
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Corresponding author

Correspondence to Shilpee Dutt.

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Competing interests

None declared.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Tata Memorial Centre institutional ethics committee (TMC-IEC III: - ECR/149/Inst/MH/2013) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Kaur, E., Goda, J.S., Ghorai, A. et al. Molecular features unique to glioblastoma radiation resistant residual cells may affect patient outcome - a short report. Cell Oncol. 42, 107–116 (2019). https://doi.org/10.1007/s13402-018-0411-7

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