Abstract IA005: Brain tumors hijack neuronal mechanisms to thrive
Authors: Frank Winkler
Journal: Cancer Research (2024)

Abstract Our nervous system is involved in the inititation, growth, dissemination, and therapy resistance of many cancer types throughout the body. In this talk I will present this emerging field of “Cancer Neuroscience”, with the example of our work on brain tumors: how incurable gliomas hijack neurodevelopmental pathways to build tumor cell networks and to colonize the brain; how neurons form synapses to tumor cells that stimulate tumor growth; and how neuro-cancer disconnection strategies are developed. A special focus will lie on the question how these discoveries can be optimally translated into the clinic. Integration into communicating tumor cell networks is a way how the entire brain tumor organism can progress in the brain, and resist therapies. It started with our discovery of ultra-long membrane protrusions, tumor microtube (TM), in tumor cells from glioblastomas and other incurable adult and pediatric glioma entities (Osswald et al., Nature 2015). These TMs are used for very effective brain invasion, and later interconnect single tumor cells to communicating and resistant multicellular networks, but also glioma cells to neurons in the brain, with neuron-glioma synapses stimulating glioma growth (Venkataramani et al., Nature 2019) and invasion (Venkataramani et al., Cell 2022). Increasing formation of these homotypic and heterotypic networks is seen with increasing glioma malignancy: lowest in low-grade oligodendrogliomas, and highest in glioblastomas and K27M mutated gliomas. The genetic reduction of GAP-43, a crucial neurodevelopmental factor that drives TM formation and function, not only deprived glioblastoma cells from the ability to form functional tumor networks, but also made radiotherapy much more effective, by and large eradicating experimental tumors from the mouse brain, which is typically not possible with radiotherapy alone. Recently, we also discovered that brain tumor networks are constantly activated by pacemaker-like glioblastoma cells residing in network hubs that generate a periodic rhythmic activity that stimulates tumor growth and resilience (Hausmann et al., Nature 2023). Consistent with the concept of tumor cell resilience by network integration, radiotherapy and also chemotherapy (Weil et al., Neuro-Oncology 2017) preferentially killed the unconnected glioblastoma cells, leaving the tumor cell networks largely intact. Damage to the tumor network by surgical measures induced a self-healing response. Taken together, integration into multicellular, highly functional, communicating, and resilient networks is not only a feature of the nervous system, but also of incurable, most aggressive brain tumors. In this talk, clinical concepts that originate from these discoveries are presented, including a network disconnection strategy currently tested in the German MecMeth trial (EudraCT2021-000708-39), and the AMPAR inhibitor perampanel as a potential inhibitor of neuron-glioma synapses. Furthermore, new basic and translational developments in the field of brain tumor networks are presented and discussed. Citation Format: Frank Winkler. Brain tumors hijack neuronal mechanisms to thrive [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr IA005.