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 Torres Fernández, Jenny Stroh, Ali T. Abdallah, Julia Beck, Lejla Mulalic, Anna Schmitt, Holger Grüll, Thorsten Persigehl, Alexander Quaas, Martin Peifer, Johannes Brägelmann, Hans Christian Reinhardt, Pascal Nieper, Robert Hänsel‐Hertsch, Roman K. Thomas, Julie George, M. Schweiger, Manolis Pasparakis, Filippo Beleggia, Silvia von Karstedt
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.