Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression
- Ariadne Androulidaki
- Fanyu Liu
- Christina M. Bebber
- Ilmars Kisis
- Vignesh Sakthivelu
- Pascal Hunold
- Lioba Koerner
- Alina Dahlhaus
- Fatma Isil Yapici
- Christina Grimm
- Alicja Pacholewska
- Sofya Tishina
- Franka Doskotz
- Lucia A. Torres Fernández
- Jenny Stroh
- Ali T. Abdallah
- Julia Beck
- Lejla Mulalic
- Anna Schmitt
- Holger Grüll
- Thorsten Persigehl
- Alexander Quaas
- Martin Peifer
- Johannes Brägelmann
- H. Christian Reinhardt
- Pascal Nieper
- Robert Hänsel-Hertsch
- Roman K. Thomas
- Julie George
- Michal R. Schweiger
- Manolis Pasparakis
- Filippo Beleggia
- Silvia von Karstedt
2025-12-18
Most neuroendocrine cancers lack caspase 8 protein expression. While this feature was thought to facilitate escape from extrinsic apoptosis, its cancer-regulatory function has remained unexplored. Here, we devise a mouse model of small cell lung cancer (SCLC) recapitulating the lack of expression of caspase 8 seen in humans and uncover an unexpected role for necroptosis-fueled pre-tumoral inflammation resulting in reprogramming towards a neuronal progenitor cell-like state and increased metastatic disease. Notably, transcriptional signatures of this cellular state are enriched in relapsed and metastatic human SCLC. Mechanistically, caspase 8 loss within the pre-tumoral niche promotes inflammation marked by increased recruitment of regulatory T cells (Tregs) which are responsible for the promotion of metastatic disease. Importantly, inactivation of the necroptosis executioner MLKL reverses pre-tumoral inflammation, decreases metastasis as well as neuronal-like reprogramming. Taken together, our findings suggest that pre-tumoral inflammatory cell death contributes to neuronal progenitor mimicry, immunosuppression and increased metastasis in SCLC.