Scientists found that a cell’s location and environment in a cancerous tumor can strongly influence which genes are active and the cell’s role in the cancer’s biology by using 3D models of ovarian cancer tumors to study gene activity. More specifically, the team, which was co-led by researchers from the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS), demonstrated that gene activity differed between cells closer to the tumor’s center and those at or near its surface.
Fluorescent dyes that spread into tumors are used in conjunction with technology to reveal the genetic activity of individual tumor cells. Researchers may be able to examine how individuals’ responses to the same disease can vary. Better treatments for cancer and other diseases could be developed as a result of this research, which could assist medical professionals in identifying targeted treatment options for tumors. On June 21, the team published their findings in Cell Systems.
A translational scientist at NCATS, Craig Thomas, Ph.D., stated, “It’s commonly accepted that a cell’s location and surrounding environment influence the cell’s identity.” It is possible for two cells to be genetically identical but have distinct cellular identities—that is, different genes are activated depending on where they are and what they are exposed to. Our objective was to develop a straightforward strategy for studying this idea in a variety of settings.”
“Two cells can be genetically identical but have different cellular identities, which means that different genes are turned on depending on their location and environment. Our goal was to develop a simple way for studying this topic in a variety of scenarios.”
Craig Thomas, Ph.D., a translational scientist at NCATS.
Segmentation by Exogenous Perfusion, or SEEP, is a new method that makes use of a dye that diffuses into cells throughout a tumor at a rate that can be determined. The cell’s location and, more specifically, its access to the environment outside the cell can be determined by measuring the amount of dye that gets into each tumor cell. The researchers were able to connect the identities of the cells to their location by connecting this data to the gene activity of the cells through computational methods.
Tuomas Knowles, Ph.D., a co-author at the University of Cambridge, stated, “Understanding the relation of cells to each other and the effects of their positions in space has been a fundamental question in cancer, neurological disorders, and other areas.”
The work made use of three kinds of 3D laboratory models made from human ovarian cancer cells: spheroids, organoids, and mouse models. Spheroids are three-dimensional clusters of cells grown in a lab dish that can resemble some characteristics of tissues and organs. Organoids, which are also grown in a dish, are more complicated, three-dimensional models that more closely resemble the structure and function of organs and tissues. Researchers implanted human ovarian cancer cells into mouse models to create tumors.
“It’s basic to comprehend that only one out of every odd cell in a growth will be presented to a medication similarly,” Knowles said. “A malignant growth medication could kill the cells on the outer layer of a cancer, but the cells in the center are unique and impacted in an unexpected way. That probably plays a role in why some treatments fail.”
The SEEP method showed that tumor cells closer to the surface of the tumor were more likely to divide than cells closer to the center of the tumor. To shield themselves from immune system responses, tumor cells on the surface also activate genes. These gene responses are linked to how the tumor hides from the body’s immune defenses, which is not surprising.
Gene activity differences between cells near the surface and deeper within the ovarian cancer tumor models surprised researchers. The findings may assist researchers in better comprehending the structure of tumors. Improved treatments could result from this information. Targeting cells that are most likely to be affected in different parts of the tumor could be one way to treat cancer.
David Morse, Ph.D., the study’s first author and medical student, said, “Certain tumor cell types are susceptible to certain therapies.” “Knowing where cells are located and their levels of accessibility in the tumor could help us decide how to use drugs in combination.” It might let us know how long to give a drug and when to try other treatments.
More information: David B. Morse et al, Positional influence on cellular transcriptional identity revealed through spatially segmented single-cell transcriptomics, Cell Systems (2023). DOI: 10.1016/j.cels.2023.05.003
