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The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells

Oncogene volume 32, pages 699–712 (2013)Cite this article

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Abstract

The aggressiveness of glioblastoma multiforme (GBM) is defined by local invasion and resistance to therapy. Within established GBM, a subpopulation of tumor-initiating cells with stem-like properties (GBM stem cells, GSCs) is believed to underlie resistance to therapy. The metabolic pathway autophagy has been implicated in the regulation of survival in GBM. However, the status of autophagy in GBM and its role in the cancer stem cell fraction is currently unclear. We found that a number of autophagy regulators are highly expressed in GBM tumors carrying a mesenchymal signature, which defines aggressiveness and invasion, and are associated with components of the MAPK pathway. This autophagy signature included the autophagy-associated genes DRAM1 and SQSTM1, which encode a key regulator of selective autophagy, p62. High levels of DRAM1 were associated with shorter overall survival in GBM patients. In GSCs, DRAM1 and SQSTM1 expression correlated with activation of MAPK and expression of the mesenchymal marker c-MET. DRAM1 knockdown decreased p62 localization to autophagosomes and its autophagy-mediated degradation, thus suggesting a role for DRAM1 in p62-mediated autophagy. In contrast, autophagy induced by starvation or inhibition of mTOR/PI-3K was not affected by either DRAM1 or p62 downregulation. Functionally, DRAM1 and p62 regulate cell motility and invasion in GSCs. This was associated with alterations of energy metabolism, in particular reduced ATP and lactate levels. Taken together, these findings shed new light on the role of autophagy in GBM and reveal a novel function of the autophagy regulators DRAM1 and p62 in control of migration/invasion in cancer stem cells.

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Acknowledgements

We thank Susan Short, Sergio Quezada, Steven Pollard and Daniel Hochhauser (UCL Cancer Institute, London, UK), Sharon Tooze (CRUK London Research Institute, London, UK), Bruno Calabretta (Kimmel Cancer Center, Philadelphia, USA), Andrea Cossarizza and Paola Loria (University of Modena and Reggio Emilia, Italy) for reagents and critical discussion. We also thank other members of PS lab (UCL Cancer Institute) and Melania Capasso (Barts and the London, UK). We thank Carol Mercer and Pat Dennis (University of Cincinnati, USA) for the BHMT plasmid, and Scott Lowe (CSHL, USA) for the hRAS-V12 IRES GFP plasmid (Addgene). Finally, we thank the UCL Scientific Services and in particular Tomas Adejumo for support with flow cytometry. PS is supported by the Samantha Dickson Brain Tumour Trust and a generous donation by David Hunter and Wendy Tansey in memory of Peter Clark. SG is recipient of a PhD studentship from the University of Modena and Reggio Emilia, Modena, Italy. CJ acknowledges NHS funding to the NIHR Biomedical Research Centre. ET acknowledges Cancer Research UK funding to his laboratory (C8851/A10844). MSR is funded by the National Hospital Development foundation and SB (Institute of Neurology, IoN) received support from UCLH CBRC (Ref 31) and the Samantha Dickson Brain tumor trust (Ref SDBTT0805). SB (IoN) acknowledges the Neurosurgical team at the National Hospital for their continued support of the brain tumor bank.

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Authors and Affiliations

  1. Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, UK

    S Galavotti, S Bartesaghi & P Salomoni

  2. Royal Veterinary College, University of London, London, UK

    D Faccenda & M Campanella

  3. Institute of Neurology, UCL, London, UK

    M Shaked-Rabi & S Brandner

  4. University of Eastern Piedmont, Novara, Italy

    S Sanzone & F Condorelli

  5. National Hospital for Neurology and Neurosurgery, London, UK

    A McEvoy

  6. MRC Toxicology Unit, Leicester, UK

    D Dinsdale

  7. UCL Consortium for Mitochondrial Research, London, UK

    M Campanella

  8. Barts Cancer Institute, London, UK

    R Grose

  9. Institute of Cancer Research, London, UK

    C Jones

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Galavotti, S., Bartesaghi, S., Faccenda, D. et al. The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells. Oncogene 32, 699–712 (2013). https://doi.org/10.1038/onc.2012.111

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