2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - ePosters-EP01.01: Low caspase 8 expression promotes neuronal progenitor mimicry and small cell lung cancer metastasis

EP01.01: Low caspase 8 expression promotes neuronal progenitor mimicry and small cell lung cancer metastasis

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The research explored the role of Caspase 8 in the development and metastasis of small cell lung cancer (SCLC). Typically, human SCLC shows epigenetic silencing of Caspase 8, a phenomenon not present in mouse models. To address this, researchers developed a novel mouse model that mimics the lack of Caspase 8 seen in humans, providing insight into the cancer's progression.<br /><br />Results indicated that the absence of Caspase 8 escalates necroptosis-driven pre-tumoral inflammation. This inflammation facilitates an immunosuppressive environment and leads to epigenetic reprogramming, pushing the cells towards a neuronal progenitor cell-like state. This transition enhances the cancer's ability to metastasize. The transcriptional signatures associated with this cellular reprogramming were found to be prominent in relapsed and metastatic human SCLC.<br /><br />Further studies involving single-nuclei sequencing highlighted significant differentials in gene expression and cellular pathways when comparing the new mouse model to traditional ones. Loss of Caspase 8 was directly connected with increased prevalence of regulatory T cells (Tregs), promoting an immunosuppressive microenvironment favorable for cancer spread.<br /><br />The research also demonstrated a potential therapeutic angle: targeting Tregs with CTLA-4 blockade reduced metastasis and improved survival outcomes in the new model. This reinforces the value of the absence of Caspase 8 as a potential indicator of aggressive SCLC and a target for therapeutic intervention.<br /><br />Overall, this study underscores the critical role of caspase 8 in SCLC progression and metastasis, offering a new perspective on human SCLC's characteristics. The findings encourage further investigation into targeted therapies that could mitigate or prevent the progression of this aggressive lung cancer subtype.

Asset Subtitle

Silvia Von Karstedt

Keywords

Caspase 8

small cell lung cancer

SCLC

epigenetic silencing

necroptosis

immunosuppressive environment

neuronal progenitor cell

metastasis

regulatory T cells

CTLA-4 blockade