Cancers are extremely heterogeneous. Even within the same tumor, some cells may be more aggressive than others. In the latest issue of Nature Cell Biology, a team of scientists led by Stein Aerts (VIB-KU Leuven Center for Brain & Disease Research) reports how distinct gene regulatory networks drive melanoma skin cancer cells to become more invasive. The findings will inform research into better cancer treatments.
Cancers are extremely heterogeneous. Not only are tumors complex mixtures of cancer cells and dozens of other different cell types, the cancer cells themselves also differ substantially, both within a given tumor (intratumoral heterogeneity) and across different tumors in the same patient (intertumoral heterogeneity).
“During cancer progression, gene expression profiles can change, causing heterogeneity in tumors. This heterogeneity has an important impact on therapy response, since some cells may be more or less vulnerable to a particular drug therapy,” says prof. Stein Aerts (VIB-KU Leuven).
Thanks to advances in single-cell technology, Aerts and his team can now study gene regulation in thousands of individual cells, enabling them to decode how genomic regulatory programs drive dynamic changes in cells.
Melanoma identity switch
One type of cancer that is notoriously heterogeneous is melanoma skin cancer. Melanoma cells typically have a high number of irreversible genetic alterations and undergo an identity switch, explains Jasper Wouters, a postdoctoral researcher in Aerts’ team:
“We know that melanoma cells are highly susceptible to phenotype switching. This is a dynamic process that involves reversible changes in gene expression that allow cells to switch between a proliferative state and an invasive state.”
To investigate the diversity of melanoma cell states, the scientists profiled the gene expression and accessibility of nearly 40,000 individual melanoma cells, derived from 10 different patients. They looked at what happens during phenotype switching, and examined intra- and intertumoral differences in gene regulation.
“We found that cancer cell heterogeneity could be largely attributed to differences in their gene regulatory networks, and that the switch from a proliferative to an invasive state is controlled by a regulatory program that is highly reproducible across distinct patient cultures,” says Wouters.
In addition to the proliferative and invasive state, there is evidence for one or more intermediate states, adds Aerts, although these have only been poorly described: “We and others in our field have wondered whether this intermediate state is really a distinct state or rather a mix of features of the proliferative and invasive states? Our analysis of melanoma cell state diversity indicates that intermediate states do exist and that they are in fact governed by distinct gene regulatory networks.”
Aerts underscores the importance of the new insights for future therapeutic developments: “The gene regulatory networks we identified may serve as new targets to try and prevent cancer cells from switching to an invasive state and thus reduce chances for metastasis or drug resistance.”
Robust gene expression programs underlie recurrent cell states and phenotype switching in melanoma, Wouters, Kalender-Atak et al. Nature Cell Biology 2020
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