Inflammation and immunosuppression promote the aggressive behavior and spread of SCLC

Inflammation and immunosuppression promote the aggressive behavior and spread of SCLC

Small cell lung cancer (SCLC) is one of the most aggressive forms of lung cancer with a five-year survival rate of just five percent. Despite this poor prognosis, SCLC initially responds well to chemotherapy. However, patients typically relapse and experience very rapid disease progression. Current research into the biological mechanisms behind SCLC remains critical to prolong treatment response, overcome relapses, and ultimately improve long-term outcomes for patients.

A research team led by Professor Dr. Silvia von Karstedt (Translational Genomics, CECAD Cluster of Excellence for Aging Research and Center for Molecular Medicine Cologne - CMMC) has discovered a novel mechanism that helps explain the aggressive nature of this type of cancer. The study, titled “Lack of Caspase 8 Directs Neuronal Progenitor-like reprogramming and Small Cell Lung Cancer Progression,” was published inNature communication.

Unlike other epithelial cancers, SCLC shares features with neuronal cells, including the lack of caspase-8 expression, a protein involved in programmed, non-inflammatory cell death (apoptosis), a mechanism essential for eliminating faulty or mutated cells and maintaining health.

To better mimic the features of human SCLC, the team created and characterized a novel genetically engineered mouse model lacking caspase-8. With this new model, the team observed that when this protein is missing, an unusual chain reaction starts. “The absence of caspase-8 leads to a type of inflammatory cell death called necroptosis, which creates a hostile, inflamed environment even before tumors fully form,” explains von Karstedt.

We were also intrigued to find that pretumor necroptosis can actually promote cancer by conditioning the immune system.”

Dr. Silvia von Karstedt, University of Cologne

The inflammation creates an environment in which the body's immune response to cancer is suppressed, preventing immune cells from attacking threats such as cancer cells. This in turn can promote tumor metastasis. Surprisingly, the researchers observed that this inflammation also causes the cancer cells to behave more like immature neuron-like cells, a condition that facilitates their spread and is associated with relapse.

While it is not yet known whether similar pretumoral inflammation also occurs in human patients, this work identifies a mechanism that contributes to patient aggressiveness and relapse in SCLC and could be used as an opportunity to improve the efficiency of future therapies and early-stage diagnostic methods.

This research was funded by the German Research Foundation as part of the Collaborative Research Center (SFB) 1399 “Mechanisms of drug sensitivity and resistance in small cell lung cancer”.

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