Scientists have a better understanding of the bully-like behavior of cancer cells that allows them to aggressively grow, overtake neighboring cells, and spread in humans. According to Creighton University cancer researcher Laura A. Hansen, PhD, key findings of a study published in the journal Nature provide new clues for how to intervene for therapy. Hansen, a co-author of the paper, said the results are likely to promote intense study of the “fitness fingerprints” on the surface of cells that play a determining role in their life and death.

The research paper was authored by Rajan Gogna, PhD, a former Creighton University School of Medicine faculty member, and Eduardo Moreono, PhD, of the Champalimaud Centre for the Unknown in Lisbon, Portugal. The paper titled, "Fitness fingerprints of human cells promote competitive growth in cancer," demonstrated for the first time in human cells that cell competition is involved in the expansion of cancer cells at the expense of their less-fit neighbors. The findings show that a human protein (called Flower) plays a role in determining cell fitness, and the development and progression of cancer.

This groundbreaking research was a continuation of Gogna’s previous study of cell competition in Drosophila, a fruit fly used in evolutionary and developmental studies that showed a direct fitness-based selection process is used to eliminate many types of viable but impaired cells in the insect. The latest research explored whether a similar selection process occurs in humans.

Results demonstrated the fitness of human cells is determined by the expression of different isoforms of the Flower gene (labeled “Win” or “Lose” in the study). Cells expressing the “Win” isoforms induced cell death in neighboring cells expressing the “Lose” isoforms, which allowed these “Winners” to grow and spread. Cancer always expresses the “Win” form of protein, forcing cells in their immediate vicinity to express the “Lose” form of protein. Using cancer cell lines, the study further revealed that cancer cells that have higher expression of the “Win” isoform grow faster and larger than cell lines that express “Lose.”

“For a cancer researcher, a lot of the ideas about the markers for cell fitness and competition that come from fruit flies made a lot of sense and could explain a lot about cancer cell behavior if we understood if that happened in humans and how that happened,” said Hansen, a professor in Creighton University’s School of Medicine and director of its Histology Core Facility. “This study went a long way to answering those questions. This is a completely new concept that leads to big conclusions.”

Hansen’s work on the study included obtaining patient samples and demonstrating that tumor cells that have high expression of the “Win” form tend to grow in areas where normal cells express the “Lose” form. The antibodies and immunostaining developed and used in the study were done in Creighton’s laboratories with the contributions of School of Medicine students Nicholas Tran and Kimberly Fazio, who also is a co-author of the research paper. Some of the cell competition and laser capture microdissection experiments, as well as analysis of data, also were conducted at Creighton.

“These findings enhance our understanding of the factors that make some tumors more aggressive than others, and our understanding of the factors that allow tumors to metastasize to specific locations,” Gogna said.

Ongoing research is continuing in Creighton’s Department of Biomedical Sciences. Justin Rudd, a third-year MD/PhD student, is focusing his on investigating Flower interactions in skin cancer and how the “Win” and “Lose” expressions are regulated by ultraviolet light, the leading cause of skin cancer.

Hansen said the discovery of a mechanism that promotes cancer cell growth through the elimination of surrounding, less-fit cells is likely to spur more experiments that aim to understand the activity of human Flower proteins.

“It’s still a black box as far as understanding how these Flower proteins act, what signaling pathways are downstream from them, and what cancers they play a role in,” Hansen said. “But now we can think of completely new ways to kill cancer by targeting these mechanisms and researching if it’s possible to inhibit Flower “Win” pathways in cancer cells, or upregulate Flower “Win” signaling in the connective tissues of an organ and suppress the growth of the cancer—those are some of the possibilities.”