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

Presented by Dr Marta Portela Esteban, La Trobe University

WNT vampirization by glioblastoma promotes JNK/MMPs positive feedback loop to
mediate glioma progression and neurodegeneration

Marta Portela, Varun Venkataramani, Natasha Fahey-Lozano, Esther Seco, Maria
Losada-Perez, Frank Winklerand Sergio Casas-Tintó*

1- Instituto Cajal-CSIC. Av. del Doctor Arce, 37. 28002. Madrid. Spain
2- Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg,
INF 400, 69120 Heidelberg, Germany
3- Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German
Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
4- Institute for Anatomy and Cell Biology, Heidelberg University, 69120 Heidelberg, Germany.
5-La Trobe University. Bundoora 3086, Victoria. Australia.
*-Corresponding author: scasas@cajal.csic.es and m.portela@latrobe.edu.au

Glioblastoma (GB) is the most lethal brain tumor due to its high proliferation,
aggressiveness, infiltration capacity and resilience to current treatments. Activation of the
Wingless-related-integration-site (WNT) pathway is associated with a bad prognosis. Using
Drosophila and primary xenograft models of human GB, we describe a mechanism that leads
to the activation of WNT signaling [Wingless (Wg) in Drosophila] in tumor cells.

GB cells display a network of tumor microtubes (TMs) which enwraps neurons,
accumulates Wg receptor Frizzled1 (Fz1), and, thereby, actively depletes Wg from the neurons.
In this context TMs emerge as a central cellular feature of GB, here we also describe a
molecular mechanism behind TMs production, infiltration and maintenance. Glial cells are
initially transformed into malignant GB upon epidermal growth factor receptor (EGFR) and
Phosphoinositide 3-kinase (PI3K) pathways constitutive activation, then GB cells establish a
positive feedback loop including Wg signaling, c-Jun N-terminal kinase (JNK) and matrix
metalloproteases (MMP). In order, Fz1 mediates Wg signaling upregulation which activates
JNK in GB cells. Therefore, JNK signaling triggers MMPs upregulation and facilitates TMs
infiltration in the brain, hence TMs network expands and promote further wingless depletion
to close the loop.

Consequently, GB cells proliferate due to β-catenin activation, and neurons degenerate
due to Wg signaling extinction. This novel view explains both neuron-dependent tumor
progression and the neural decay associated with GB.

1) Portela M*, Fahey-Lozano N and Casas-Tintó S*. (2019). Wingless promotes JNK/MMPs positive
feedback loop mediate tumour microtubes expansion, glioma progression and neurodegeneration.
BioRxiv 520346; doi: https://doi.org/10.1101/520346. *Co-Senior Authors. Under revision in PLoS
Biol Journal.

2) Portela M*, Venkataramani V, Fahey-Lozano N, Seco E, Losada-Perez M, Winkler F and Casas-
Tintó S*. (2018). Active wingless vampirization by glioblastoma network leads to brain tumor growth
and neurodegeneration. BioRxiv 428953; doi: https://doi.org/10.1101/428953. *Co-Senior Authors.
Under revision in PLoS Biol Journal.