Cancer cells don’t just shape shift. They state shift. That is, they can embody different cell states, or types, that possess different degrees of plasticity or hereditability. If cancer cells become highly plastic, they can cause cancer cell populations to become more diverse and difficult to suppress. That is, as cell types proliferate, some of the cell types that emerge will enhance treatment resistance and metastatic spread.
To date, plasticity has been conceived qualitatively. But now, a quantitative approach is available in the form of a tool called Phylogenetic Analysis of Trait Heritability, or PATH. For a sample of tumor cells, it quantifies the plasticity of each cell state, based on how often a cell in that state gives rise to progeny cells that share that state. Cell states that are less likely to be inherited are considered more plastic.
PATH was developed by a scientific team led by Dan A. Landau, MD, PhD, an associate professor at Weill Cornell Medical College and a core member of the New York Genome Center. Landau and colleagues introduced PATH in Nature Genetics, in an article titled, “Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution.” In this article, Landau and colleagues describe how PATH can be used to “quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data.”
“Applying PATH to a mouse model of pancreatic cancer, we observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states,” the article’s authors wrote. “In primary glioblastoma, we identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, we reconstructed a phylogeny from single-cell whole-genome sequencing in B cell acute lymphoblastic leukemia and delineated the heritability of B cell differentiation states linked with genetic drivers.”
Essentially, the scientists used PATH to quantify the plasticity of tumor cells from animal models and human patients. Out of this work came the key finding: a transitional cell state in glioblastoma.
“Plasticity is a tremendous enabler of cancer spread and treatment resistance, and we expect this new tool to give us critical insights into those processes—insights we hope to use to fight cancers more effectively,” said Landau, the current study’s senior author. The study’s co-first authors, all from the Landau Laboratory, were Joshua Schiffman, PhD, a postdoctoral fellow; Andrew D’Avino, an MD-PhD student; and Tamara Prieto, PhD, a postdoctoral fellow.
Plasticity is normal and widespread in the earliest stages of life, as cells mature from embryonic, stem-cell states to increasingly differentiated states with highly specialized functions. Some degree of plasticity is also needed in mature tissues for repair and maintenance functions. Cancers unfortunately tend to hijack these latent plasticity mechanisms, and cancers exhibiting more plasticity tend to be harder to treat successfully.
To study how plasticity contributes to the branching off of cell lineages—that is, to somatic evolution—researchers need single-cell lineage tracing data. And obtaining such data usually requires the use of DNA markers that show which cells are descended from the same mother cell. Researchers also need information on individual cell states, which can be defined however an investigator prefers.
“It can be based on the cells’ patterns of gene activity, their surface receptors, their spatial locations in the tumor, or really anything you can dream up,” Schiffman said.
The researchers demonstrated PATH in analyses of pancreatic tumors, revealing new details of how these tumors exploit a form of plasticity called the epithelial-to-mesenchymal transition, in which cells of the epithelial type turn into cells of the mesenchymal type—thereby acquiring migratory properties that enable metastatic spread.
“It was known that there was a transition with intermediate states, but it wasn’t known exactly what was going on,” Schiffman said. “We were able to provide a clearer picture of those dynamics.”
Similarly, for glioblastoma cells from human patients, PATH-based analysis showed how the tumor cells toggle back and forth between more stem-like and mesenchymal states, using a state resembling that of a brain helper-cell called an astrocyte as a key intermediate state. Finally, the team’s PATH-augmented profiling of malignant B cells from leukemia patients uncovered an apparent link between certain DNA mutations in the leukemia cells and a relatively plastic, stem-like cell state defined by a key surface receptor.
All in all, the researchers said, PATH provides a very useful new framework for studying how tumors develop.
Landau, Schiffman, and their colleagues envision a number of PATH-based clinical applications. These include prognostic tests based on the degree of plasticity measured in tumor samples—more plasticity being a reason to expect more tumor aggressiveness—and new treatments that would target the more stable, least plastic cell states in tumors. The researchers also plan to perform PATH-based analyses of tumor samples before and after different treatments, to determine, for example, which treatments can reduce tumor cell plasticity.
