Novel global cooperative phenomena of cell interactions discovered in cervical cancer cells

A Japanese research team has discovered a novel global cooperative phenomena of cell interactions in cervical cancer cells. Their findings suggest that the cells are metabolically connected in a functional network. The framework they used in their studies could prove useful for investigating the hidden state of a group of cells.

The research is published in the journal Scientific Reports on March 3, 2025.

The team discovered a novel global cooperative phenomenon, a hidden causal interaction network, in monolayers of HeLa cervical cancer cells that exhibited metabolic oscillations. HeLa cells are human cells that were derived from cervical cancer cells taken from a cancer patient in 1951. They are the first immortal human cell line and have been a vital tool in medical research. 

These metabolic oscillations in cancer cells describe rhythmic fluctuations. They occur in the concentrations of metabolites within the glycolytic pathway, that is, the reactions that occur as glucose is converted. Scientists often observe these rhythmic fluctuations in cancer cells, especially those with high glycolytic activity. These oscillations can provide insights into the metabolic activity of cancer cells and potentially their interactions with other cells in the tumor microenvironment. "Knowledge of these 'cancer-cell hubs' may pave the way for novel cancer therapies," said Takashi Amemiya, a professor at Yokohama National University.

The term global cooperative phenomena describes patterns or behaviors that occur when individual elements within a system interact. The global cooperative phenomena the team discovered exhibited characteristics of a broad-scale network. "This suggests that key cells perform a hub-like function in the network and that the population of HeLa cells forms a metabolically connected functional network rather than a randomly connected one," said Amemiya. The team discovered the hidden network structure by analyzing the causality between the oscillating cells using a statistical method called Convergent Cross Mapping.

The framework proposed in this study is useful for investigating the hidden state of a group of cells and can accelerate studies on cellular metabolic phenomena including metabolic oscillations in beta cells within islets of Langerhans."

Takashi Amemiya, Professor, Yokohama National University

Islets of Langerhans are cell clusters that work together to regulate the body's blood sugar levels. The team's framework could also be applied to systems of weakly coupled oscillators that may include hidden cooperative phenomena.

Much remains to be learned about cancer cell metabolism. Until this team studied HeLa cervical cancer cells in 2017, there had been no studies that reported evidence of metabolic oscillations in cancer cells in individual cell levels. The cells oscillated independently and exhibited no synchronization in their oscillations. "We assumed that the cell-cell interactions were too weak to induce synchronization, however such weak and hidden cell-cell interactions can be revealed through the analysis of the causality of oscillations by the Convergent Cross Mapping method." This method is based on the phase-space reconstruction of time-series data. The researchers use it to find causality in weakly coupled components of nonlinear dynamical systems.

Looking ahead, the team notes that the characteristics of a broad-free network can be applied to the causal metabolic interaction in cancer. They suggest that the causal interaction of glycolytic oscillations in the HeLa cells was probably because of the exchange of a lactate. Thus, a complex lactate-mediated symbiosis network may emerge in the cancer microenvironment in the human body. In addition, metabolic symbiosis is known to enhance cancer malignancy by providing opportunities for cancer cells to obtain their energy efficiently from other cells or adapt to tissue microenvironments. "Our goal is to find a novel way for cancer therapies based on the knowledge of 'cancer-cell hubs,' which can break the possible networks of energy symbiosis in cancer," said Amemiya.

The research team includes Takashi Amemiya, Ikuma Fujita, and Kenichi Shibata from YOKOHAMA National University; Susumu Shuto from YOKOHAMA National University and Toshiba Electric Devices & Storage Corp.; Kazuyuki Nakamura and Tomohiko Yamaguchi from Meiji University; and Masatoshi Watanabe from Mie University.

The research is funded by grants from JSPS KAKENHI and MEXT Pro­motion of Distinctive Joint Research Center Program, and a cooperative research project from YOKOHAMA National University.