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

doi:10.1038/s41467-025-67142-4

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Article number	11280
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-67142-4
Publication status	Published - 18 Dec 2025
Externally published	Yes

Keywords

Animals
Lung Neoplasms/pathology
Small Cell Lung Carcinoma/pathology
Humans
Caspase 8/genetics
Mice
Disease Progression
Neural Stem Cells/metabolism
Cellular Reprogramming/genetics
Necroptosis
T-Lymphocytes, Regulatory/immunology
Disease Models, Animal
Inflammation
Mice, Inbred C57BL
Male
Female

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10.1038/s41467-025-67142-4

Cite this

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., ... von Karstedt, S. (2025). Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression. Nature Communications, 16(1), Article 11280. https://doi.org/10.1038/s41467-025-67142-4

@article{ccbf03283a534ab7915e01c9c7fa2f77,

title = "Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression",

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.",

keywords = "Animals, Lung Neoplasms/pathology, Small Cell Lung Carcinoma/pathology, Humans, Caspase 8/genetics, Mice, Disease Progression, Neural Stem Cells/metabolism, Cellular Reprogramming/genetics, Necroptosis, T-Lymphocytes, Regulatory/immunology, Disease Models, Animal, Inflammation, Mice, Inbred C57BL, Male, Female",

author = "Ariadne Androulidaki and Fanyu Liu and Bebber, \{Christina M.\} and Ilmars Kisis and Vignesh Sakthivelu and Pascal Hunold and Lioba Koerner and Alina Dahlhaus and Yapici, \{Fatma Isil\} and Christina Grimm and Alicja Pacholewska and Sofya Tishina and Franka Doskotz and \{Torres Fern{\'a}ndez\}, \{Lucia A.\} and Jenny Stroh and Abdallah, \{Ali T.\} and Julia Beck and Lejla Mulalic and Anna Schmitt and Holger Gr{\"u}ll and Thorsten Persigehl and Alexander Quaas and Martin Peifer and Johannes Br{\"a}gelmann and Reinhardt, \{H. Christian\} and Pascal Nieper and Robert H{\"a}nsel-Hertsch and Thomas, \{Roman K.\} and Julie George and Schweiger, \{Michal R.\} and Manolis Pasparakis and Filippo Beleggia and \{von Karstedt\}, Silvia",

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = dec,

day = "18",

doi = "10.1038/s41467-025-67142-4",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

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Androulidaki, A, Liu, F, Bebber, CM, Kisis, I, Sakthivelu, V, Hunold, P, Koerner, L, Dahlhaus, A, Yapici, FI, Grimm, C, Pacholewska, A, Tishina, S, Doskotz, F, Torres Fernández, LA, Stroh, J, Abdallah, AT, Beck, J, Mulalic, L, Schmitt, A, Grüll, H, Persigehl, T, Quaas, A, Peifer, M, Brägelmann, J, Reinhardt, HC, Nieper, P, Hänsel-Hertsch, R, Thomas, RK, George, J, Schweiger, MR, Pasparakis, M, Beleggia, F & von Karstedt, S 2025, 'Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression', Nature Communications, vol. 16, no. 1, 11280. https://doi.org/10.1038/s41467-025-67142-4

TY - JOUR

T1 - Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression

AU - Androulidaki, Ariadne

AU - Liu, Fanyu

AU - Bebber, Christina M.

AU - Kisis, Ilmars

AU - Sakthivelu, Vignesh

AU - Hunold, Pascal

AU - Koerner, Lioba

AU - Dahlhaus, Alina

AU - Yapici, Fatma Isil

AU - Grimm, Christina

AU - Pacholewska, Alicja

AU - Tishina, Sofya

AU - Doskotz, Franka

AU - Torres Fernández, Lucia A.

AU - Stroh, Jenny

AU - Abdallah, Ali T.

AU - Beck, Julia

AU - Mulalic, Lejla

AU - Schmitt, Anna

AU - Grüll, Holger

AU - Persigehl, Thorsten

AU - Quaas, Alexander

AU - Peifer, Martin

AU - Brägelmann, Johannes

AU - Reinhardt, H. Christian

AU - Nieper, Pascal

AU - Hänsel-Hertsch, Robert

AU - Thomas, Roman K.

AU - George, Julie

AU - Schweiger, Michal R.

AU - Pasparakis, Manolis

AU - Beleggia, Filippo

AU - von Karstedt, Silvia

PY - 2025/12/18

Y1 - 2025/12/18

N2 - 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.

AB - 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.

KW - Animals

KW - Lung Neoplasms/pathology

KW - Small Cell Lung Carcinoma/pathology

KW - Humans

KW - Caspase 8/genetics

KW - Mice

KW - Disease Progression

KW - Neural Stem Cells/metabolism

KW - Cellular Reprogramming/genetics

KW - Necroptosis

KW - T-Lymphocytes, Regulatory/immunology

KW - Disease Models, Animal

KW - Inflammation

KW - Mice, Inbred C57BL

KW - Male

KW - Female

UR - https://www.scopus.com/pages/publications/105025403149

U2 - 10.1038/s41467-025-67142-4

DO - 10.1038/s41467-025-67142-4

M3 - Article

C2 - 41413044

AN - SCOPUS:105025403149

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 11280

ER -

Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression

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Keywords

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