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Low caspase 8 expression promotes neuronal progenitor mimicry and small cell lung cancer metastasis

ABSTRACT: Mimicry of neuronal features is emerging as malignant regulator of cancer growth and metastasis. Neuroendocrine (NE) cancers including small cell lung cancers (SCLC) have been shown to share expression profiles marking various stages of neuronal differentiation. Yet, how these state changes are caused and malignant consequences thereof have remained unexplored.Here, we devise a novel mouse model of SCLC recapitulating low expression of caspase 8 as seen in humans and uncover that this allows for epigenetic reprogramming towards a more aggressive and metastasising stem-cell like neuronal state, resembling neuronal intermediate progenitor cells (nIPCs). Notably, transcriptional signatures of this cellular state are enriched in relapsed and metastatic human SCLC. Mechanistically, caspase 8 loss within the pre-tumoral niche promoted immunosuppression and metastasis via induction of immunogenic cell death. Inactivation of the necroptosis executioner Mixed lineage kinase domain-like protein (MLKL) neutralised caspase 8 loss-induced immunosuppression, metastasis and diminished the stem-cell like state providing genetic evidence for a role of necroptosis in promoting these effects. Collectively our data uncover an unexpected role for low expression of caspase 8 in directing neuronal-like reprogramming towards an immunosuppressive and highly metastatic state in SCLC.

ORGANISM(S): Mus musculus

PROVIDER: GSE274809 | GEO | 2025/11/05

REPOSITORIES: GEO

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Low caspase 8 expression promotes neuronal progenitor mimicry and small cell lung cancer metastasis

Project description:Mimicry of neuronal features is emerging as malignant regulator of cancer growth and metastasis. Neuroendocrine (NE) cancers including small cell lung cancers (SCLC) have been shown to share expression profiles marking various stages of neuronal differentiation. Yet, how these state changes are caused and malignant consequences thereof have remained unexplored.Here, we devise a novel mouse model of SCLC recapitulating low expression of caspase 8 as seen in humans and uncover that this allows for epigenetic reprogramming towards a more aggressive and metastasising stem-cell like neuronal state, resembling neuronal intermediate progenitor cells (nIPCs). Notably, transcriptional signatures of this cellular state are enriched in relapsed and metastatic human SCLC. Mechanistically, caspase 8 loss within the pre-tumoral niche promoted immunosuppression and metastasis via induction of immunogenic cell death. Inactivation of the necroptosis executioner Mixed lineage kinase domain-like protein (MLKL) neutralised caspase 8 loss-induced immunosuppression, metastasis and diminished the stem-cell like state providing genetic evidence for a role of necroptosis in promoting these effects. Collectively our data uncover an unexpected role for low expression of caspase 8 in directing neuronal-like reprogramming towards an immunosuppressive and highly metastatic state in SCLC.

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Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

Project description:Caspase-8 and FADD play key roles in the regulation of cell death by necroptosis. The absence of either protein results in early embryonic lethality due to the activation of the kinase RIPK3 and its phosphorylation of the necroptosis executioner, MLKL. We genetically engineered and characterized a mouse model to monitor MLKL phosphorylation in the absence of necroptosis in vivo. Ablation of caspase-8 or FADD resulted in the transcriptional upregulation in several tissues of ZBP1, a cytosolic nucleic acid sensor capable of activating RIPK3, and ZBP1 was required for spontaneous phosphorylation of MLKL. Our findings provide a novel mechanism by which the FADD-Caspase-8 complex prevents necroptosis.

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Project description:Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase 8-independent form of programmed cell death called necroptosis. Once Receptor Interacting serine/threonine Protein Kinase 3 (RIPK3) is activated by upstream cell death signals, it phosphorylates MLKL and triggers the oligomerization and membrane translocation required for MLKL induced membrane disruption. Besides phosphorylation, MLKL also undergoes ubiquitylation during the early stages of necroptosis, yet neither the mechanism nor the significance of this event has been demonstrated. Here we show that necroptosis-specific, multi-mono-ubiquitylation of MLKL occurs on biological membranes, and requires its activation and oligomerisation. Inactive MLKL mutants recruited to membranes during necroptosis are ubiquitylated but this results in their proteasome and lysosome dependent turnover. We identified several ubiquitylated lysines however mutation of these did not affect MLKL ubiquitylation in response to a necroptotic stimulus.

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Project description:Small cell lung cancer (SCLC) is a disease characterized by aggressive clinical behavior and lack of effective therapy. Due to its high tendency of early dissemination, only a third of patients have limited-stage disease at the time of diagnosis. SCLC is thought to derive from neuroendocrine cells of the lung. Although several molecular abnormalities in SCLC have been described, there are relatively few studies on epigenetic alterations in this type of tumor. Here, we have used methylation profiling with the methylated CpG island recovery assay (MIRA) in combination with microarrays and conducted the first genome-scale analysis of methylation changes that occur in primary SCLC and SCLC cell lines. Among hundreds of tumor-specifically methylated genes, we identified 73 gene targets that are methylated in more than 77% of primary SCLC tumors, most of which have never been linked to aberrant methylation in tumors. These targets have excellent potential for development of biomarkers for early detection of SCLC. SCLC cell lines had an ~3-fold greater number of hypermethylated genes than primary tumors. Gene ontology analysis indicated a significant enrichment of methylated genes functioning as transcription factors and in processes of neuronal differentiation. Motif analysis of tumor-specific methylated regions identified enrichment of binding sites for several neural cell fate-specifying transcription factors including NEUROD1, HAND1, ZNF423 and REST. We hypothesize that functional inactivation of their corresponding binding sites by DNA methylation can lead to an escape route for early progenitor cells towards the malignant state and may contribute to the origin of SCLC. Comparison between healthy and SCLC tumor DNA methylation profiles

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