A team of researchers at the Istituto Italiano di Tecnologia (IIT) in Milan has developed a novel approach to pinpoint cells responsible for initiating tumors and driving metastasis, with a focus on triple-negative breast cancer. By combining genetic barcoding with single-cell sequencing technologies, the group tracked the evolution of cancer cells and identified those capable of resisting chemotherapy—before these traits were even observable in patients. These results, supported by the AIRC Foundation, were published in Nature Communications.
Triple-negative breast cancer, which represents about 20% of all breast cancer cases, is notoriously difficult to treat. Researchers at IIT’s Center for Genomic Sciences, led by Francesco Nicassio, focused on tracing the origins of this aggressive cancer and its evolution over time. Using genetic barcodes—tools more often associated with commercial product tracking—the team labeled individual cancer cells, allowing them to follow the cells' behavior throughout tumor progression.
Tracking Cellular Evolution with Genetic Barcodes
The concept of genetic barcoding allowed the team to assign unique molecular labels to each cancer cell, effectively tracking their behavior as the tumor grew and metastasized. This approach provided the researchers with a method to map out a detailed evolutionary pathway of the cancer cells and identify which ones were selected during the development of the tumor. Nicassio highlighted the multidisciplinary effort involved, stating that “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.”
The researchers aimed to identify tumor-initiating cells, which are pivotal in the early stages of cancer formation and metastasis, but notoriously hard to detect. Through the combination of single-cell sequencing and barcoding techniques, the team was able to isolate metastasis-promoting and chemo-resistant cells, facilitating molecular characterization.
Dissecting Cancer’s Molecular Features with Multi-Omic Technologies
Central to the research was the use of multi-omic technologies to study the cancer cells' genetic, epigenetic, and transcriptional characteristics. This simultaneous investigation allowed the researchers to uncover critical epigenetic changes that influence tumor behavior without altering the underlying DNA sequence. These modifications—known as epigenetic markers—are crucial in shaping gene expression and were found to play a vital role in the formation of metastases.
A significant finding from the study was the identification of a so-called "pro-metastatic epigenome," a unique molecular signature within the primary tumor. This signature marks the most aggressive cells—those that are more likely to spread and form secondary tumors. Matteo Marzi, a co-author of the paper, explained the significance of this discovery, saying, “We identified a ‘pro-metastatic epigenome,’ a kind of molecular signature present in the primary tumor that marks the most aggressive cells.”
This molecular signature not only enabled the researchers to distinguish aggressive, metastasis-driving cells but also allowed them to differentiate these cells from a separate population that develops drug resistance due to genetic mutations.
Uncovering the Link Between Genetics and Chemotherapy Resistance
One of the study’s critical aspects was understanding how certain cells could evade chemotherapy treatment. Using their single-cell sequencing approach, the team was able to finely characterize individual cells’ molecular profiles, observing features that were previously only speculative. Co-author Francesca Nadalin, from both IIT and the European Bioinformatics Institute (EMBL-EBI) in Cambridge, UK, noted, “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.”
This analysis of the genome and epigenome revealed specific regions of the genome that may contribute to cancer proliferation and drug resistance. The results suggest that genetic mutations and epigenetic markers combine to create cellular environments where certain cells not only survive chemotherapy but continue to evolve and potentially initiate further metastases.
Looking Forward: Expanding the Research
The research team’s next goal is to validate their findings in a broader range of cultured cells. They hope to deepen their understanding of how molecular profiles influence cancer properties, such as metastasis and chemotherapy resistance. Although the results could eventually lead to new diagnostic methods or therapeutic treatments, the immediate focus remains on exploring the basic molecular mechanisms that contribute to these dangerous cancer traits.
Original Publication
Nadalin, F., Marzi, M.J., Pirra Piscazzi, M. et al. Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution. Nat Commun 15, 7609 (2024). https://doi.org/10.1038/s41467-024-51424-4
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