Universität zu Köln

Touet, Marian (2026). Functional neuron-cancer synapses in small cell lung cancer: from structural validation to mechanistic insights and therapeutic implications. PhD thesis, Universität zu Köln.

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Abstract

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer with a dismal prognosis. Increasing evidence indicates that crosstalk between the nervous system and cancer plays a pivotal role in tumor initiation, progression, and therapy resistance. Direct synaptic contacts between the central nervous system (CNS) and gliomas have been described; however, no evidence of synapses between the nervous system and extracranial malignancies has been reported to date. Here, we demonstrate that SCLC cells form bona fide synapses with neurons. A genome-wide in vivo piggyBac transposon screen, followed by cross-species genomic and transcriptomic validation, identified neuronal, synaptic, and glutamatergic gene sets as key features of SCLC biology. High-resolution microscopy, transsynaptic rabies-tracing, and electrophysiological recordings provided both structural and functional evidence for synaptic contacts and transmission between neurons and SCLC cells. Various in vitro proliferation assays showed that SCLC cells derive a proliferation advantage from neurons, which is at least partially mediated by neuronal activity and spatial proximity. Furthermore, targeting glutamate signaling in an autochthonous mouse model of SCLC conveys therapeutic efficacy. This work establishes neuron-SCLC synapses as a novel, functionally important, and targetable paradigm of SCLC. More broadly, this work provides ‘proof-of-principle’ that peripheral cancers can integrate into neuronal networks via synaptic contacts, extending this paradigm beyond the CNS.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Touet, Marian mariantouet@gmail.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-815088
Date:	2026
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Cancer neuroscience English Small cell lung cancer English Synapses English
Date of oral exam:	2 September 2026
Referee:	Name Academic Title Reinhardt, H. C. Universitätsprofessor Dr. med. Heger, J.-M. Privatdozent Dr. med. Winkler, F. Professor Dr. med.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81508