Tumor evolution is written in the genome

Milan (Italy), October 14, 2024 – Using a system of genetic barcodes and a novel single-cell sequencing method, a research team at the Istituto Italiano di Tecnologia (IIT-Italian Institute of Technology) in Milan has developed an approach to identify cells responsible for initiating tumors and metastasis, particularly in breast cancer. With these same techniques, the researchers also discovered which of these cells are capable of resisting chemotherapy, even before these characteristics appear in patients. The findings, supported by the AIRC Foundation, have been published in the prestigious journal Nature Communications.

Barcodes are typically used to identify commercial products and track their movements. However, the IIT research group at the Center for Genomic Sciences in Milan, led by Dr. Francesco Nicassio, employed them for a more unconventional purpose: to label cancer cells and track their evolution over time. The study specifically focused on triple-negative breast cancer, which accounts for about 20% of breast cancer cases. This form of cancer is difficult to treat, presenting a significant challenge for both therapy and research. Genetic labels were assigned to individual cancer cells from triple-negative breast cancer, allowing researchers to trace their evolutionary path during tumor development and growth. This approach enabled the creation of a distinct and recognizable profile for the cells that are selected in the resulting cancer.

"Identifying the so-called tumor-initating cells is not easy, but thanks to close multidisciplinary collaboration and the use of cutting-edge multi-omic technologies—particularly single-cell sequencing—we were able to achieve this result," explains Dr. Nicassio, who led the research. "Based on the molecular characteristics we identified, we could select the tumor cells capable of forming metastases and those able to develop drug resistance."

The next step involved studying the genetic aspects of the tracked cells, including their genetic, epigenetic, and transcriptional features. The researchers developed a multi-omic method, an innovative approach to study these characteristics simultaneously. The results revealed that epigenetic features—modifications that, while not altering the DNA or RNA sequence, can influence gene expression—play a critical role in both the initial development of the tumor and the formation of metastases.

“We identified a ‘pro-metastatic epigenome,’ a kind of molecular signature present in the primary tumor that marks the most aggressive cells,” adds Dr. Matteo Marzi from the Center for Genomic Sciences at IIT in Milan, one of the paper’s authors.

Through these molecular signatures, the researchers were able to classify cells as more or less aggressive and distinguish them from another population of cells that develop drug resistance due to genetic mutations.

“Our work primarily involved finely characterizing the molecular profiles of individual cells, using innovative technologies to observe and understand what we could previously only hypothesize,” explains co-author Dr.  Francesca Nadalin, a researcher at both IIT in Milan and the European Bioinformatics Institute (EMBL-EBI) in Cambridge, UK. “The results suggest that specific regions of the genome may be involved in the development of specific cancer properties, such as tumor proliferation or chemotherapy resistance.”

The research team aims to deepen their investigation, with the goal of eventually introducing these findings into clinical practice. These results could serve as a cornerstone for new early diagnostic methods and innovative therapeutic treatments. The next steps include validating the findings on a broader range of cultured cells and further understanding the link between molecular profiles and the underlying causes of metastasis and drug resistance.

The research study has been conducted in the framework of IIT’s RNA Flagship initiative.