A powerful new analytical tool offers a closer look at how tumor cells "shape-shift" to become more aggressive and untreatable, as shown in a study from researchers at Weill Cornell Medicine and the New York Genome Center.
A tumor cell shape-shifts by changing its cell type or state, thus altering its basic pattern of activity and perhaps even its appearance. This changeability or "plasticity" is a characteristic of cancer that leads to diverse tumor-cell populations and ultimately the emergence of cell types enabling treatment resistance and metastatic spread.
The new tool, described Sept. 24 in a paper in Nature Genetics, can be used to quantify this plasticity in samples of tumor cells. The researchers demonstrated it with analyses of tumor samples from animal models and human patients, identifying, for example, a key transitional cell state in glioblastoma, the most common form of brain cancer.
"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 study senior author Dr. Dan Landau, a professor of medicine in the division of hematology and medical oncology at Weill Cornell Medicine, and a core faculty member of the New York Genome Center.
The study's co-first authors, all from the Landau Laboratory, were Joshua Schiffman, a postdoctoral fellow; Andrew D'Avino, an MD-PhD Student; and Tamara Prieto, 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.
The researchers call their new tool "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.
To apply PATH in an analysis of a given cell population, researchers need "lineage" information - usually based on DNA markers - showing which cells are descended from the same mother cell. They 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, who is also a member of Weill Cornell Medicine's Englander Institute for Precision Medicine and Sandra and Edward Meyer Cancer Center, and 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.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profile for Dr. Dan Landau.
The research reported in this story was supported by the National Heart Lung and Blood Institute, the National Cancer Institute, the National Human Genome Research Institute, Center of Excellence in Genomic Science, all part of the National Institutes of Health; and the National Institutes of Health Common Fund Somatic Mosaicism Across Human Tissues.
Jim Schnabel is a freelance writer for Weill Cornell Medicine.
