SCLC: Deciphering the unusual aggressiveness of small cell lung cancer

Small cell lung cancer (SCLC) is one of the most recalcitrant cancers. SCLC patients usually present with extensive metastases at diagnosis, and treatments are largely ineffective for prolonged tumor control, resulting in an average survival of less than a year.

Professor Jin-Shing Chen from the Department of Surgery at National Taiwan University Hospital (NTUH) and his team participated in an international study that uncovered key mechanisms driving SCLC aggressiveness. These findings were published online in Nature. This pioneering study unveiled that the self-generated electrical activity of SCLC directly promotes tumor metastasis and progression. The new insights may provide new avenues for SCLC treatment in the future.

Moving forward, we hope to continue investigating how the cancer cells harness energy, uncover their metabolic vulnerabilities, and explore new therapeutic strategies
Leanne Li

The study was led by Dr. Leanne Li’s laboratory at the Francis Crick Institute in the UK. In addition to the Crick and the NTUH team, this study also involved researchers from the University of Cambridge, MIT, Harvard Medical School, Dana-Farber Cancer Institute and UT Southwestern Medical Center.

Dr. Li received her MD from NTU, and worked with Professor Jin-Shing Chen’s team during her medical training at NTUH. “Dr. Chen’s profound contribution has changed the landscape of lung cancer research and patient care in Taiwan, which really inspired me,” she said. The connection has led to a long-term collaboration with Professor Chen’s group. “It is an honor to collaborate with my mentor from my alma mater, who is also the best thoracic surgeon in Taiwan."

SCLC consists of neuroendocrine (NE) cells and non-neuroendocrine (non-NE) cancer cells. This study showed that NE cells can generate intrinsic electrical signals, similar to how brain cells send commands. More importantly, this electrical activity directly drives tumor aggression. Meanwhile, non-NE cells function as supportor cells for energy supply. This cooperation between NE and non-NE cells facilitates SCLC growth and metastasis.

Portrait photo of Professor Jin-Shing Chen

Professor Jin-Shing Chen, Chairman of the Department of Surgery at NTUH, used an analogy to explain the phenomenon: “Ordinary cancer cells are like cars—they require external fuel or charging to function. By cutting off their fuel or power supply, cancer progression can often be suppressed. However, SCLC is unique in the sense that it seems to be able to install its own solar panels, creating an internal electrical grid for self-sustaining energy production. This ability to generate its own power makes SCLC even more aggressive and harder to treat.”

To confirm that the intrinsic electrical activity of cancer cells contributes to tumor progression, the research team used tetrodotoxin (TTX), a neurotoxin that inhibits neuronal activity, to suppress the cancer cells' ability to fire. The results showed that while TTX did not immediately kill NE cells, it significantly reduced their ability to form tumors over time. Finally, analysis of SCLC patient samples also suggested that patients with more electrically active cancers are associated with worse prognosis, confirming that NE cells’ intrinsic electrical activity drives tumor growth and metastasis. This mechanism is a key factor in disease progression and patient mortality.

Dr. Li further explained: “While it was previously known that some cancer cells can resemble nerve cells at gene expression level, this is one of the first proofs that their electrical activity can directly drive tumor progression. This is a breakthrough in cancer research, and we suspect that highly malignant SCLC may share similarities with other highly metastatic cancers. Therefore, it is very likely that what we’ve found in SCLC may provide insights applicable to other cancer types as well. Moving forward, we hope to continue investigating how the cancer cells harness energy, uncover their metabolic vulnerabilities, and explore new therapeutic strategies.”

Building on these findings, the NTU research team plans to further investigate how similar electrophysiological mechanisms influence other cancer types. They will also assess whether targeting cancer cells’ self-sustaining neural electrical networks could lead to innovative treatment approaches, potentially achieving groundbreaking progress in overcoming hard-to-treat cancers.

Source: National Taiwan University Hospital

12.03.2025