Cell to cell communication mediates glioblastoma progression in Drosophila

Abstract

Glioblastoma (GB) is the most aggressive and lethal tumour of the central nervous system (CNS). GB cells grow rapidly and display a network of projections (ultra-long tumour microtubes (TMs)), that mediate cell to cell communication. GB-TMs infiltrate throughout the brain, enwrap neurons and facilitate the depletion of the signalling molecule wingless (Wg)/WNT from the neighbouring healthy neurons. GB cells establish a positive feedback loop including Wg signalling upregulation that activates cJun N-terminal kinase (JNK) pathway and matrix metalloproteases (MMPs) production, which in turn promote further TMs infiltration, GB progression and neurodegeneration. Thus, cellular and molecular signals other than primary mutations emerge as central players of GB. Using a Drosophila model of GB, we describe the temporal organization of the main cellular events that occur in GB, including cell to cell interactions, neurodegeneration and TMs expansion. We define the progressive activation of JNK pathway signalling in GB mediated by the receptor Grindelwald (Grnd) and activated by the ligand Eiger (Egr)/TNFα produced by surrounding healthy brain tissue. We propose that cellular interactions of GB with the healthy brain tissue precede TM expansion and conclude that non-autonomous signals facilitate GB progression. These results contribute to deciphering the complexity and versatility of these incurable tumours.

JNK Pathway in CNS Pathologies

“…Recent findings in Drosophila demonstrate that GB aggressiveness correlates with JNK pathway progressive activation [ 42 ]. First, the tumor induces neurodegeneration, followed by an infiltration through the brain with ultralong extended glial membrane protrusions known as cytonemes (mimicking mammal tumor microtubes, TMs), and GB cell proliferation [ 42 , 43 , 44 ]. The glial network mediates cell-to-cell communication, and promotes the exchange of molecules between neurons and GB cells.…”

“…The glial network mediates cell-to-cell communication, and promotes the exchange of molecules between neurons and GB cells. Consequently, the JNK pathway is activated in GB cells and promotes GB progression and infiltration [ 30 , 42 , 45 ].…”

“…MMPs mediate extracellular matrix (ECM) degradation, and therefore facilitate TM infiltration [ 30 ]. Thus, the expansion of the TM network promotes communication among cells, maintaining a positive loop [ 30 , 42 ]. The Drosophila JNK ligand Egr is expressed in neurons under physiological conditions, but in GB samples, there is a progressive increase of JNK-pathway activation via the Grnd receptor by a relocalization of the ligand from neurons to glial cells [ 42 ].…”

“…Thus, the expansion of the TM network promotes communication among cells, maintaining a positive loop [ 30 , 42 ]. The Drosophila JNK ligand Egr is expressed in neurons under physiological conditions, but in GB samples, there is a progressive increase of JNK-pathway activation via the Grnd receptor by a relocalization of the ligand from neurons to glial cells [ 42 ]. Consistently with the tumor chronogram, the relocalization of Egr to glial cells coincides with the synapse loss, as a previous event to tumor infiltration and proliferation.…”

“…JNK-pathway inhibition through Egr or Grnd knockdown experiments rescue tumor proliferation and invasiveness in Drosophila [ 42 ]. Similarly, in vitro and in vivo experiments showed that the JNK inhibitors SP600125 and AS602801 impaired GB self-renewal and tumor-initiating potential [ 37 , 49 ].…”