Single-Cell Profiling Technique Could Guide Early Cancer Detection

Cancer often develops silently over many years, as individual cells acquire mutations that give them a growth advantage long before a tumor forms. These pre-malignant cells can exist alongside normal cells with no visible differences, making early detection and intervention extremely difficult. While blood-based studies have offered some insight, solid tissues have remained largely inaccessible due to technical limitations. Researchers have now demonstrated a method that can simultaneously track cancer-driving DNA mutations and their biological effects in thousands of individual cells from human tissue.

In research led by Weill Cornell Medicine (New York, NY, USA), in collaboration with New York Genome Center (New York, NY, USA), the team developed a new single-cell approach that profiles both genotype and gene activity in solid tissues. The method, created with industry collaboration, allows sensitive detection of multiple cancer driver mutations while simultaneously measuring how those mutations influence cell state, growth, and survival within each cell.

Image: Single-cell sequencing reveals how early cancer-driving mutations alter gene activity in individual cells within human tissue (Photo courtesy of Shutterstock)

The technology, known as single-cell Genotype-to-Phenotype sequencing, is optimized for solid tissue samples, which are typically difficult to analyze due to storage conditions and cellular complexity. The workflow is automated and scalable, allowing for the analysis of thousands of cells in parallel. By linking mutation status with gene expression in the same cell, the approach provides a direct view of how specific genetic changes reshape cellular behavior long before cancer develops.

The researchers applied the method to esophageal tissue from six older adults, profiling more than 10,000 individual cells. Over half of the cells carried cancer-associated driver mutations, most commonly in the NOTCH1 gene, which regulates cell maturation and survival. Cells with NOTCH1 mutations showed impaired differentiation and persistent proliferation. Additional mutations in TP53 were also identified, with affected cells displaying increased division and disrupted maturation.

The findings, published in Cancer Discovery, confirm that pre-cancerous clonal mosaicism is widespread in aging tissues and that single mutations can subtly but measurably alter cellular behavior without causing cancer outright. These insights support the idea that cancer develops through a stepwise accumulation of mutations over time. The researchers plan to expand this approach to other tissues to identify high-risk mutation patterns and explore whether targeting specific pre-malignant clones could enable early cancer prevention or risk stratification.

“This is a technological demonstration that opens up many new avenues of scientific research and even allows us to start thinking about therapeutic strategies,” said study senior author Dr. Dan Landau. “Can we target these clones in aging tissues to prevent cancer? Can we identify the types of driver mutations that are more likely to give rise to cancer and thus are worth treating? These are questions that people in the field are now asking.”

Related Links:
Weill Cornell Medicine
New York Genome Center