Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration

Abstract

Glioblastoma (GB) is the most lethal brain tumor, and Wingless (Wg)-related integration site (WNT) pathway activation in these tumors is associated with a poor prognosis. Clinically, the disease is characterized by progressive neurological deficits. However, whether these symptoms result from direct or indirect damage to neurons is still unresolved. Using Drosophila and primary xenografts as models of human GB, we describe, here, a mechanism that leads to activation of WNT signaling (Wg in Drosophila) in tumor cells. GB cells display a network of tumor microtubes (TMs) that enwrap neurons, accumulate Wg receptor Frizzled1 (Fz1), and, thereby, deplete Wg from neurons, causing neurodegeneration. We have defined this process as “vampirization.” Furthermore, GB cells establish a positive feedback loop to promote their expansion, in which the Wg pathway activates cJun N-terminal kinase (JNK) in GB cells, and, in turn, JNK signaling leads to the post-transcriptional up-regulation and accumulation of matrix metalloproteinases (MMPs), which facilitate TMs’ infiltration throughout the brain, TMs’ network expansion, and further Wg depletion from neurons. Consequently, GB cells proliferate because of the activation of the Wg signaling target, β-catenin, and neurons degenerate because of Wg signaling extinction. Our findings reveal a molecular mechanism for TM production, infiltration, and maintenance that can explain both neuron-dependent tumor progression and also the neural decay associated with GB.

Modeling invasion patterns in the glioblastoma battlefield

“…An improvement of this growth term should take into account the influence of morphogenic signaling pathways, such as Sonic Hedgehog (Shh) or Wnt (see (12,17,18,(20)(21)(22)(23) for further details). We will try to address this point in future works.…”

“…Glial cells respond to this oncogenic transformation and reproduce all main features of the disease, including glial expansion and invasion, but in a shorter period of time. This Drosophila model has been used for drug and genetic screenings and the results have been validated in human GB cells (REFs) (12)(13)(14).Agents involved in the battlefield GB growth and migration are driven by specific signaling pathways as well as interactions between the tumor and its extracellular microenvironment. In our study, we include the cell membrane protrusions (TMs) as driving factors of tumor progression, as well as cell response to signaling gradients and the interplay with the Extra Cellular Matrix (ECM).…”

“…Protease profiling studies have indicated that the expression of serine proteases, cysteine proteases and matrix metalloproteases (MMPs), the most prominent family of proteinases associated with tumorigenesis, increase in high-grade astrocytoma compared with normal brain. In particular, increased MMP levels and tumor invasiveness in human GBs show a strong correlation (12,30,31). Several studies reported their localization in TM membrane (32,33), especially for MMP-2 and MT1-MMP.Our interest arises from the analysis of the role of TMs in tumor progression and of the effect of different drugs on their structures and dynamics (34,35).…”

“…Glial cells respond to this oncogenic transformation and reproduce all main features of the disease, including glial expansion and invasion, but in a shorter period of time. This Drosophila model has been used for drug and genetic screenings and the results have been validated in human GB cells (REFs) (12)(13)(14).…”

“…Our results are supported by experimental measurements in a Drosophila model of human GB, in continuous (chemotaxis) components of the tumor microenvironment. Cytonemes are one type of filopodia, first observed in the Drosophila wing imaginal disc (16) (see also (17)(18)(19)(20)(21)(22)(23)); also known as TMs in the context of GB, they have an important role in tumor development (12). Specifically, we focus on TM involvement in the GB front progression and on their relationship with integrins and proteases.…”