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Published on: November 27, 2016
Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression
Ariadne Androulidaki1,2, Fanyu Liu1,2, Christina M Bebber1,2
1Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
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.
Insights
Loss of caspase 8 in neuroendocrine cancers fuels inflammation and promotes tumor growth. This necroptosis-driven inflammation reprograms cells, increasing metastasis and immune suppression in small cell lung cancer (SCLC).
Area of Science:
- Oncology
- Immunology
- Cell Death Research
Background:
- Neuroendocrine cancers, particularly small cell lung cancer (SCLC), often lack caspase 8 expression.
- This deficiency was traditionally linked to apoptosis evasion but its broader role in cancer progression was unknown.
Purpose of the Study:
- To investigate the functional role of caspase 8 loss in SCLC pathogenesis.
- To explore the mechanisms linking caspase 8 deficiency to tumor progression and metastasis.
Main Methods:
- Development of a genetically engineered mouse model of SCLC with absent caspase 8 expression.
- Analysis of pre-tumoral inflammation, cellular reprogramming, and metastatic spread.
- Investigated the role of necroptosis and regulatory T cells (Tregs).
- Utilized MLKL inactivation to assess necroptosis-dependent pathways.
Main Results:
- Caspase 8 loss promoted necroptosis-driven pre-tumoral inflammation.
- This inflammation led to reprogramming towards a neuronal progenitor cell-like state.
- Increased recruitment of regulatory T cells (Tregs) was observed, promoting metastasis.
- Inactivation of MLKL reversed inflammation, reduced metastasis, and neuronal reprogramming.
Conclusions:
- Pre-tumoral inflammation, fueled by necroptosis due to caspase 8 loss, drives SCLC progression.
- This process contributes to neuronal progenitor mimicry, immune suppression via Tregs, and enhanced metastatic potential.
- Targeting necroptosis or associated inflammation may offer therapeutic strategies for SCLC.
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