Oral Presentation ANZSCDB National Scientific Meeting 2019

WNT vampirization by glioblastoma promotes JNK/MMPs positive feedback loop to mediate glioma progression and neurodegeneration (62509)

Marta Portela Esteban 1 2 , Varun Venkataramani 3 , Natasha Fahey-Lozano 1 , Esther Seco 2 , Maria Losada-Perez 2 , Frank Winkler 3 , Sergio Casas-Tinto 2
  1. Cell Polarity and Signalling Laboratory 315 LIMS2. Biochemistry and Genetics Department. , La Trobe University, 3086 Bundoora, Melbourne, VIC, Australia
  2. Molecular, Cellular and Developmental Neurobiology Department, Cajal Institute of Neurobiology, CSIC, Madrid, Spain
  3. Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 , Heidelberg, Germany

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*, 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.
  2. 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.