Insight into tumor evolution through combined measurements in individual cells

Tumors can develop through genetic changes in individual cells. During each cell cycle – when the cell divides into two daughter cells – the DNA of the new cells can become slightly different from their predecessor, for example through the introduction of DNA mutations or changes in the structure or packaging of the DNA. Due to these genetic changes, no cell is exactly the same.
When a cell quickly diverges from its predecessor through cell divisions, it can give rise to a tumor. Even within such a tumor, there is great variation between cells, which is called intra-tumor heterogeneity (ITH). ITH plays a key role in the development of cancer but also in therapy resistance: where one cell of the tumor may respond to a certain treatment, another may not.

Characterizing ITH

Characterization of ITH is therefore crucial for obtaining insight into the evolution of the tumor and – ultimately – for deciding the best way to treat it. However, the methods that were previously available could take a snapshot of the tumor, but not track its growth process over time. This provided a limited view on ITH, as it for example lacks information about the order in which the genetic changes that gave rise to the tumor occurred. Newer methods allow researchers to study one genetic modification at a time, but cannot combine measurements of multiple modalities at once. Reason enough for the group of Alexander van Oudenaarden to develop a new technique.

Organoid models

The researchers used an organoid model of colorectal cancer. Organoids are tiny 3D structures in a dish that mimic the development of the disease. Buys de Barbanson, co-first author of the new paper in Cell Genomics, explains: “Using these organoids, we were able to track the evolution of colorectal tumors for half a year in the lab. We obtained multiple measurements from individual cells in parallel. In other words, we could see the genetic changes happening in different cells at the same time.”

Loss of chromosomes

“We observed that multiple cells undergo the same genetic changes during the development of colorectal cancer: they lose chromosome 4, but only after they already lost chromosome 18. These losses enable the cells to multiply faster, thereby becoming the dominant clone in the culture,” says Lennart Kester, other co-first author of the paper. This combination of chromosome deletions was also present in the clinical data of patients with colorectal cancer, which validates the organoids as a suitable model for research into this type of cancer. “The model is very useful to look into actual tumors. As a next step, researchers could for example use the organoids to test different treatment options and see which cells respond and which do not,” De Barbanson adds.

Therapy resistance

The results provide insight into the development of colorectal tumors and indicate that the order in which genetic changes occur is important for tumor progression. Furthermore, the study contributes to our fundamental knowledge about (cancer) biology and brings forward a new technology to study it in the lab. In the future, the results may be applied to tackle therapy resistance of tumors.

Publication

“Integration of multiple lineage measurements from the same cell reconstructs parallel tumor evolution.” Lennart Kester, Buys de Barbanson, Anna Lyubimova, Li-Ting Chen, Valérie van der Schrier, Anna Alemany, Dylan Mooijman, Josi Peterson-Maduro, Jarno Drost, Jeroen de Ridder and Alexander van Oudenaarden. Cell Genomics, 2022.

Cover art

Additionally, Buys de Barbanson created the cover art for issue 2(2) of Cell Genomics. The cover illustration represents a clonal evolution tree, in which the branches represent the different genetic clones in the organoids. The colored symbols represent individual cells.