Researchers at the Institute for Research in Biomedicine of Barcelona (IRB Barcelona), located at the Barcelona Science Park, reveal that the most commonly used computational approaches may overlook key information when studying how cells interact within tissues. By combining spatial transcriptomics data with single-cell data in cancer, brain, and heart tissues, the study shows that many predicted cellular interactions do not correspond to their actual proximity within the tissue. The work, published in the journal Genome Biology, highlights the need to develop more advanced tools to understand how cells coordinate in health and disease.

The study, led by researchers Elena Pareja and Dr. Patrick Aloy from the Structural Bioinformatics and Network Biology group at IRB Barcelona, questions the reliability of current strategies used to predict cell-to-cell communication. The researchers integrated single-cell RNA sequencing data with spatial transcriptomics from breast cancer tissue, cerebral cortex, and heart tissue to systematically analyse how each cell’s environment influences its genetic activity and its interactions with neighbouring cells.

Their analyses revealed that cells of the same type showed no significant differences in their global gene expression, despite being in different tissue contexts. Furthermore, the most popular computational tools used for predicting cell communication—by identifying ligand and receptor genes—frequently indicated interactions between cell types that were not even in close proximity within the tissue.

“These findings are a wake-up call for the field because they show that if we truly want to understand how cells coordinate their functions, we need models that integrate spatial information much more rigorously,” states Dr. Patrick Aloy, ICREA researcher and group leader at IRB Barcelona.

The study suggests that while current methods are useful for proposing potential molecular interactions, they are insufficient to reflect how the local microenvironment dictates actual cell-to-cell dialogue. The authors emphasize the importance of developing new computational approaches that can more accurately identify context-dependent interactions. This is essential for unravelling complex processes such as tissue development, regeneration, and disease progression.

» Article of reference: Systematic assessment of microenvironment‑dependent transcriptional patterns and intercellular communication. Elena Pareja‑Lorente and Patrick Aloy. Genome Biology (2025) doi: 10.1186/s13059-025-03677-5

» Link to the news: IRB Barcelona website [+]