Journal Article

DKFZ-2025-03001

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression.

Androulidaki, A. ; Liu, F. ; Bebber, C. M. ; Kisis, I. ; Sakthivelu, V. ; Hunold, P. ; Koerner, L. ; Dahlhaus, A. ; Yapici, F. I. ; Grimm, C. ; Pacholewska, A. ; Tishina, S. ; Doskotz, F. ; Torres Fernández, L. A. ; Stroh, J. ; Abdallah, A. T. ; Beck, J. ; Mulalic, L. ; Schmitt, A. ; Grüll, H. ; Persigehl, T. ; Quaas, A. ; Peifer, M. ; Brägelmann, J. ; Reinhardt, F. C.DKFZ* ; Nieper, P. ; Hänsel-Hertsch, R. ; Thomas, R. K. ; George, J. ; Schweiger, M. R. ; Pasparakis, M. ; Beleggia, F. ; von Karstedt, S.

2025
Springer Nature [London]

Abstract: 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.

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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