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

Sep 23, 2026

Uploaded by nayy☆

Most neuroendocrine cancers show little or no caspase 8 protein. The study builds a mouse model of small cell lung cancer that matches this caspase 8 deficiency and reveals a necroptosis-driven, pre-tumoral inflammatory program. This program reprograms tumor cells toward a neuronal progenitor-like state and accelerates metastatic progression. Caspase 8 loss increases recruitment of regulatory T cells, promoting metastasis, while MLKL inactivation reverses inflammation, reduces metastasis, and limits neuronal-like reprogramming.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Background and clinical relevance

Mouse model of small cell lung cancer with caspase 8 loss

Necroptosis-fueled pre-tumoral inflammation and neuronal-like reprogramming

Increased regulatory T cell recruitment

Mechanistic validation via MLKL inactivation

Biological and clinical implications for metastasis

Article [https://doi.org/10.1038/s41467-025-67142-4](https://doi.org/10.1038/s41467-025-67142-4) Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression Received: 22 September 2025 | Accepted: 24 November 2025 | | --- | | | | Check for updates | Ariadne Androulidaki1,2, Fanyu Liu1,2, Christina M. Bebber 1,2, Ilmars Kisis 1, Vignesh Sakthivelu 1, Pascal Hunold 3, Lioba Koerner 2,4, Alina Dahlhaus 1,2, Fatma Isil Yapici 1,2, Christina Grimm 3,5, Alicja Pacholewska 3,5, Sofya Tishina 1,2, Franka Doskotz 1,2, Lucia A. Torres Fernández 1, Jenny Stroh1,2, Ali T. Abdallah2,6,7, Julia Beck1,2, Lejla Mulalic1,2, Anna Schmitt2,8, Holger Grüll9, Thorsten Persigehl9, Alexander Quaas10, Martin Peifer 1,3, Johannes Brägelmann 1,3,11, H. Christian Reinhardt 12, Pascal Nieper1,8, Robert Hänsel-Hertsch 3, Roman K. Thomas 1,10, Julie George 1,13, Michal R. Schweiger 3,5, Manolis Pasparakis 2,3,4, Filippo Beleggia 1,8,11 & Silvia von Karstedt 1,2,3 Most neuroendocrine cancers lack caspase 8 protein expression. While this feature was thought to facilitate escape from extrinsic apoptosis, its cancerregulatory 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 humanSCLC. Mechanistically, caspase8loss 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 pretumoral 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. Small cell lung cancer (SCLC) is amongst the most aggressive forms of lung cancer with a 5-year survival rate of only 5%1. Despite this dismal prognosis, SCLC is initially highly sensitive to chemotherapy in most cases, but patients inevitably relapse with very rapid progression. SCLC unlike other epithelial cancers is thought to arise from a distinct cellular population of pulmonary neuroendocrine cells (PNECs) which share features with neuronal cells2,3. Normal neural stem or progenitor cells were shown to lack caspase 8 expression4 suggesting this to be a characteristic neuroendocrine (NE) feature. Indeed, lack of caspase-8 expression is frequently observed in other NE cancer entities, including neuroblastoma, medulloblastoma, and glioblastoma5. Human SCLC, but not non-small cell lung cancer (NSCLC) cell lines, lacked caspase 8 expression and, asa result ofthis, were resistant to induction of extrinsic apoptosis6. DNA hypermethylation within the caspase 8 gene promoter region was found in SCLC primary tumors and carcinoid tumor samples, indicating epigenetic rather than genetic loss7. A full list of afﬁliations appears at the end of the paper. e-mail: [s.vonkarstedt@uni-koeln.de](s.vonkarstedt@uni-koeln.de) a b c d e CASP8_NM033356 (FPKM) f 0 1 2 3 4 5 Sum Methylation (Reg. 4-8) hNSCLC hSCLCmNSCLCmSCLC % of mice with tumor 150 100 50 0 j metastasis no metastasis p=0.0359 RP RPC % of total mice 150 100 50 0 dead RP RPC NCAM ASCL1 CD31 CD45 Fig. 1 | Lack of caspase 8 expression promotes metastatic disease. a Caspase 8 protein expression (log2) of SCLC patients (n = 112) and matched adjacent normal lung samples (n = 112)18 is plotted. b Caspase 8 expression transcripts per kilobase million (TPM) (log2 TPM+1) in lung adenocarcinoma (TCGA; LUAD, n

FAQs

What is the main observation about caspase 8 in neuroendocrine cancers?

Most neuroendocrine cancers lack caspase 8 protein expression, and this study shows that caspase 8 loss has an unanticipated cancer-regulatory function.

How does caspase 8 loss influence small cell lung cancer progression?

Caspase 8 deficiency in the pre-tumoral niche promotes necroptosis-driven inflammation, drives reprogramming toward a neuronal progenitor-like state, and increases metastatic disease.

What effect does blocking necroptosis executioner MLKL have?

Inactivation of MLKL reverses pre-tumoral inflammation, decreases metastasis, and reduces neuronal-like reprogramming.

Sep 23, 2026

Uploaded by nayy☆