Dartmouth Research Finds Common Cancer Drug Increases Collagen in Melanoma

Newswise — The presence of collagen in the tumor microenvironment, essentially where the tumor lives, can be either good or bad according to Constance Brinckerhoff, PhD who led the Dartmouth team’s reporting of “The BRAFV600E inhibitor, PLX4032, increases type 1 collagen synthesis in melanoma cells,” in Matrix Biology Journal.

“Vemurafenib usually suppresses expression of genes in melanoma cells,” explained Brinckerhoff. “Surprisingly, we found that expression of collagen was substantially increased by melanoma cells treated with this drug.”

Vemurafenib (experimental version PLX4032) is a widely-used drug in the treatment of melanoma in patients who harbor a mutation in the BRAF gene. Signals sent by mutant BRAF protein affect many genes.

The goal of this study was to understand how the drug affects collagen synthesis by the tumor cells. Collagen is the most abundant protein in the human body, and investigators are uncertain how its presence affects the behavior of melanoma cells.

“Our findings were replicated in three melanoma cell lines and in murine melanoma cells that are a model for human disease,” said Brinckerhoff. “They were also replicated with in vivo experiments where mice harboring melanomas were fed chow with or without the drug and we also saw increased collagen in the tumors in these mice.”

Brinckerhoff’s team found the results of the study to be unexpected given that Vemurafenib suppresses expression of many genes, but only a few genes have found to be upregulated by Vemurafenib. That it was seen to increase collagen expression is unexpected, exciting, and potentially innovative.

Looking forward, Brinckerhoff is repeating and extending the studies in mice with the goal of assessing whether the increase in collagen deposition is a “good” or a “bad” effect. Reports in the literature are controversial; some suggest that collagen synthesis aids the tumor, while others say it is bad for the tumor, leading to the concept that collagen is a “double-edged sword” in tumor progression. The question is whether Vemurafenib, the common drug for patients with BRAFV600E melanoma, is helping to slow down tumor progression, or is an off-target effect of the drug.

The team used Dartmouth’s Pathology and Translational Shared Resource to perform Masson-Trichome staining of tumor tissue to allow them to look at collagen in the tumor microenvironment. The Dartmouth Biostatistics Shared Resource assisted in statistical analysis. Outside investigators are welcome to use Dartmouth’s Shared Resources by arrangement.

Brinckerhoff is the former Nathan Smith Professor of Medicine and of Biochemistry, and a previous Associate Dean for Science Education at Dartmouth’s Geisel School of Medicine. Her work in cancer is facilitated by Dartmouth’s Norris Cotton Cancer Center where she is a member of the Cancer Mechanisms Research Program.

Funding for this work was provided by NIH R01 AR-26599 and CA-77267 (CEB); NCCC pilot project (CEB), NIH P30 - Center for Molecular, Cellular and Translational Research (P30RR032136), NIH T32 – Immunology Training Grant AI007363 (MHJ/DWM), and NIH R01 CA134799 (DWM).

About Norris Cotton Cancer Center at Dartmouth-Hitchcock Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute’s “Comprehensive Cancer Center” designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.