Lack of Caspase 8 Directs Neuronal Progenitor-like reprogramming and Small Cell Lung Cancer Progression

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. Overall design: In order to investigate the role of low Caspase 8 in SCLC development we generated RP mice with conditional deletion of Caspase 8 (RPC mice) and induced tumor by adeno cre inhalation. Next, from endpoint SCLC tumors of RP and RPC mice we generated cell lines (four of each genotype) and perfomed Methyl-seq analysis in order to identify the effect of Caspase 8 deletion in RP tumor cells