Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression
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.
Authors
- Lioba Koerner (ORCID: https://orcid.org/0000-0003-4364-479X)
- Thorsten Persigehl (ORCID: https://orcid.org/0000-0001-5928-4405)
- Robert Hänsel‐Hertsch (ORCID: https://orcid.org/0000-0002-2835-4471)
- Ilmars Kisis (ORCID: https://orcid.org/0000-0001-6207-3991)
- Hans Christian Reinhardt (ORCID: https://orcid.org/0000-0001-5706-9349)
- Silvia von Karstedt (ORCID: https://orcid.org/0000-0002-7816-5919)
- Filippo Beleggia (ORCID: https://orcid.org/0000-0003-0234-7094)
- Ariadne Androulidaki
- Sofya Tishina (ORCID: https://orcid.org/0000-0002-8232-496X)
- Alexander Quaas (ORCID: https://orcid.org/0000-0002-3537-6011)
- Ali T. Abdallah (ORCID: https://orcid.org/0000-0002-8768-3232)
- Alina Dahlhaus (ORCID: https://orcid.org/0000-0001-9055-0695)
- Pascal Nieper (ORCID: https://orcid.org/0000-0003-0607-3561)
- Fanyu Liu (ORCID: https://orcid.org/0000-0002-6154-4971)
- Christina M. Bebber (ORCID: https://orcid.org/0000-0002-7841-7493)
- M. Schweiger (ORCID: https://orcid.org/0000-0002-2139-3478)
- Roman Kurt Thomas (ORCID: https://orcid.org/0000-0001-9132-4876)
- Fatma Isil Yapici (ORCID: https://orcid.org/0009-0004-9298-8315)
- Vignesh Sakthivelu (ORCID: https://orcid.org/0009-0000-1652-0850)
- Holger Grüll (ORCID: https://orcid.org/0000-0002-0993-9300)
- Martin Peifer (ORCID: https://orcid.org/0000-0002-5243-5503)
- Julia Beck (ORCID: https://orcid.org/0009-0001-3683-0431)
- Anna Schmitt (ORCID: https://orcid.org/0009-0002-7655-1805)
- Lucia Torres Fernández (ORCID: https://orcid.org/0000-0002-8890-6258)
- Manolis Pasparakis (ORCID: https://orcid.org/0000-0002-9870-0966)
- Pascal Hunold (ORCID: https://orcid.org/0000-0002-7087-5908)
- Johannes Brägelmann (ORCID: https://orcid.org/0000-0002-1306-2169)
- Christina Grimm (ORCID: https://orcid.org/0000-0002-4676-8870)
- Alicja Pacholewska (ORCID: https://orcid.org/0000-0002-4888-4883)
- Lejla Mulalic
- Julie George (ORCID: https://orcid.org/0000-0002-4272-3683)
- Jenny Stroh
- Franka Doskotz (ORCID: https://orcid.org/0009-0001-9353-4639)
Institutions
- University of Cologne (DE)
- Essen University Hospital (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-18
- DOI
- https://doi.org/10.1038/s41467-025-67142-4
- Citations
- 1
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.81