Model identifies genes that induce normal skin cells to become abnormal

Northwestern University researchers have developed a novel, three-dimensional model that allows scientists to observe how interacting with the microenvironment of metastatic melanoma cells induces normal skin cells to become similar to aggressive cancer cells that migrate and spread throughout the body.

The model, developed by Mary J. C. Hendrix and colleagues at Children’s Memorial Research Center, consists of a three-dimensional collagen matrix preconditioned by malignant melanoma cells. Hendrix is president and scientific director of the Children’s Memorial Research Center, professor of pediatrics at Northwestern University Feinberg School of Medicine and a member of the executive committees of The Robert H. Lurie Comprehensive Cancer Center and the Center for Genetic Medicine at Northwestern University.

The model was described in an article in the Nov. 15 issue of Cancer Research.

“Our findings offer new insights into the influence of the tumor cell microenvironment on the transformation of normal skin cells, as well as on genetic triggering mechanisms and signaling pathways that could be targeted for novel therapeutic strategies to inhibit the spread of melanoma,” Hendrix said.

Metastatic cancer cells are characterized by increased tumor cell invasion and migration, as well as an undifferentiated, or “plastic,” nature.

The Hendrix lab has hypothesized that this poorly differentiated cell type serves as an advantage to aggressive cancer cells by enhancing their ability to metastasize virtually undetected by the immune system. The group’s current study tested the hypothesis that the microenvironment of metastatic melanoma cells could induce benign skin cells to become cancer-like.

The researchers seeded a particularly aggressive form of human metastatic melanoma cells onto a three-dimensional collagen matrix and allowed the cells to precondition the microenvironment for several days. The malignant melanoma cells were removed and the matrix was left intact.

Then, normal human skin cells were seeded onto the melanoma-preconditioned matrix and were allowed to remain for several days.

After this period, the previously normal cells seeded onto the matrix preconditioned by the metastatic melanoma were reprogrammed to express genes (produce specific gene proteins) associated with a highly plastic cell type similar to the aggressive melanoma cells used in the study.

Removal of the “transdifferentiated” skin cells from the melanoma microenvironment caused the cells to revert to their original appearance.

“There were no significant genetic changes between normal skin cells grown on an untreated matrix and those exposed to a matrix preconditioned by human metastatic melanoma cells, further supporting the hypothesis that “epigenetic” induction of changes in skin cell gene expression is directly related to exposure to the metastatic microenvironment,” the authors said.

Hendrix’s co-researchers on the study were Elizabeth A. Seftor; Kevin M. Brown; Lynda Chin; Dawn A. Kirshmann; William W. Wheaton; Alexei Protopopov; Bin Feng; Yoganand Balagurunathan; Jeffrey M. Trent; Brian J. Nickoloff; and Richard E. B. Seftor, from Northwestern University; Harvard Medical School; Tgen; and Loyola University.