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A recent study conducted by researchers at the Francis Crick Institute has unveiled a remarkable characteristic of certain aggressive lung cancer cells: they can establish their own electric network similar to the nervous system. This discovery sheds light on how these cancer cells may operate with increased independence from their surrounding environment, potentially facilitating a more efficient spread within the body.
Small cell lung cancer (SCLC) is particularly notorious for its treatment challenges, as it often metastasizes by the time of diagnosis. This cancer type originates predominantly from neuroendocrine (NE) cells, which play a critical role in regulating airflow and blood circulation in the lungs.
In a publication in Nature, the research team from the Crick Institute aimed to explore whether electrical activity in SCLC, present in human and mouse samples, could be linked to the cancer’s aggressive nature.
Employing techniques from neuroscience, the researchers discovered that SCLC cells had essentially disconnected from the body’s primary electrical network. They demonstrated the ability to generate their own electrical impulses, effectively forming an autonomous electrical network within the tumor itself.
Fueling the Cancer Cells
Given that generating electrical signals demands significant energy, the researchers delved into how this energy was produced. They observed notable changes in gene expression as the cancer progressed, with some cells losing their NE properties and transitioning into non-neuroendocrine (non-NE) cancer cells.
It was evident that these cancer cells cooperated to facilitate tumor growth. The NE cells activated genes associated with electrical communications, while the non-NE cells initiated genes that created a nurturing environment. The interactions between NE cells and non-NE cells resembled the dynamics observed between neurons and astroglia in the brain — with non-NE cells acting as support entities, transferring lactate to the NE cells as a secondary energy source. Blocking this lactate transport resulted in a significant decrease in NE cells’ electrical activity, implying that this inter-cellular relationship is vital for tumor sustenance.
Linking Electrical Activity to Tumor Aggression
Despite possessing similar genetic alterations responsible for cancer, the investigators found that non-NE cells in mice did not spread or induce additional tumors. To further evaluate the contribution of electrical activity to NE cells, they utilized tetrodotoxin (TTX), a toxin derived from puffer fish that inhibits electrical activity. The application of TTX did not kill NE cells in vitro, yet it significantly diminished their long-term tumor-forming capacity, without affecting non-NE cells.
The team then analyzed molecular indicators of heightened electrical activity in a group of SCLC patients, discovering that these indicators were markedly increased in cancerous cells in contrast to surrounding healthy tissues. Additionally, as the disease progressed, the non-NE cells displayed characteristics of lactate secretion. This shift in energy utilization among NE cells is distinct from many other types of cancer that lack this ability to establish their own electrical frameworks.
Collectively, these findings point to the critical role of electrical activity in NE cells as a driver for tumor proliferation and metastasis, which constitutes a significant factor in cancer-related mortality.
Paola Peinado Fernandez, a postdoctoral fellow and one of the leading authors of the study, stated, “Our research demonstrates that NE cells in SCLC can transition to an ‘off-grid’ energy model, creating their own electrical supply while also receiving support from non-NE cells, a mechanism that could enhance the cancer’s aggressiveness and complicate treatment strategies.”
Leanne Li, head of the Cancer-Neuroscience Laboratory at the Crick Institute, added, “While it has been known that some cancer cells can exhibit neural-like behavior, our research establishes a clearer connection between the development of an independent electrical network and disease progression. By applying a cross-disciplinary approach, we are able to gain fresh insights into this affliction.”
Moving forward, the research team plans to investigate the role of electrical activity in other cancer types, as well as explore the potential of targeting this feature in small cell lung cancer to uncover new therapeutic avenues.
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