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.
Highlights
Glioblastoma multiforme (GBM) represents one of the leading cancer-related deaths in both the pediatric and adult populations, with median survival being on average little over a year
We identified high levels of DRAM1 expression to correlate with a shorter overall survival time across all subclasses and within the mesenchymal subtype in particular (Figure 1d)
The main findings of our study are: (i) high expression of autophagy-associated factors, such as DRAM1 and p62, is found in GBM patients belonging to the mesenchymal subclass,[6,43] which defines aggressiveness and invasion;[7] (ii) DRAM1 expression correlates with poor overall survival; (iii) in primary tumors and GBM stem cells (GSCs), autophagy is associated with activation of the RAS/MAPK pathway; (iv) DRAM1 and p62 regulate energy metabolism and cell migration/invasion in GSCs
Summary
Glioblastoma multiforme (GBM) represents one of the leading cancer-related deaths in both the pediatric and adult populations, with median survival being on average little over a year. This dismal prognosis is caused by different factors. Suppression of the mesenchymal signature severely impairs tumor invasion and progression in preclinical models,[7] suggesting that this signature may enhance the invasive capacity of GBM cells. These studies suggest that therapy directed against these distinct molecular features could represent significant advance in GBM treatment.
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