Age-related transformations in fibroblasts, cells integral to the skin’s structure, play a role in the formation of aggressive and treatment-resistant melanoma in men, a new study reveals.
New research indicates that age-related transformations in fibroblasts—cells that form the structure of skin—contribute to the emergence of aggressive, treatment-resistant melanoma in males, according to findings from the Johns Hopkins Kimmel Cancer Center.
The study was published online on September 6 in Cell.
The likelihood of developing melanoma, an extremely serious type of skin cancer, rises with age. Men are at a higher risk compared to women, and they often experience more aggressive forms that are difficult to treat, especially as they grow older, explains Ashani Weeraratna, Ph.D., a Bloomberg Distinguished Professor, E.V. McCollum Professor, and head of the Department of Biochemistry and Molecular Biology at Johns Hopkins. Yash Chhabra, Ph.D., who is now an assistant professor at Fox Chase Cancer Center in Philadelphia, also played a key role in the study.
Weeraratna and her team have shown that changes in normal cells surrounding tumor cells—the tumor microenvironment—related to aging can affect cancer outcomes. They aimed to determine whether differences in aging and sex could influence the noted disparities in melanoma based on sex.
“Melanoma is significantly more aggressive in men than in women,” Weeraratna elaborates. “Do normal surrounding cells age differently in men compared to women?”
Fibroblasts are responsible for producing collagen, which provides the skin with structure and durability. Previous research by Weeraratna and her team demonstrated that age-related alterations in fibroblasts facilitate the spread of melanoma cells, resulting in poorer outcomes. Their latest findings confirm that the aging process in fibroblasts differs between men and women, and the changes occurring in male fibroblasts lead to more aggressive and harder-to-treat melanomas.
Upon transplanting melanoma cells into aged male or female mice, researchers noted a greater accumulation of DNA damage in cells from male mice, regardless of whether the tumor cells were male or female.
“It’s not about the male or female tumor cells themselves,” she clarifies. “The age-related changes happening in male fibroblasts within the tumor microenvironment explain the variations in DNA damage.”
In experiments analyzing aged human male and female fibroblasts, they discovered that male fibroblasts accumulated reactive oxygen species, which cause stress and damage to cells. They also found that aged male fibroblasts produced increased levels of bone morphogenic protein 2 (BMP2), a protein typically associated with the development of bone and cartilage.
Increasing BMP2 production through genetic or recombinant protein methods led melanoma cells to become more invasive and resistant to targeted cancer therapies. Conversely, inhibiting BMP2 production with a natural blocker rendered these cells more responsive to cancer treatments in both male and female mice.
This study has critical implications for cancer research. Currently, the majority of preclinical studies on cancer are conducted using younger mice. Weeraratna emphasizes the need to study cancer in older mice and aging human cells to gain more accurate insights.
“Understanding whether men and women have different responses to treatments is crucial, and we need to better customize therapies to address age and sex-related differences,” she adds.
Weeraratna and her team are now investigating how age and sex-related changes in immune cells surrounding melanoma tumors impact their responses to immune-enhancing treatments that are increasingly used in melanoma therapy. They also aim to explore similar age- and sex-related changes in other types of cancer, such as pancreatic cancer.
Other contributors to the study include Sneha Pramod, Daniel J. Zabransky, Vania Wang, Agrani Dixit, Ruzhang Zhao, Edwin Kumah, Megan L. Brezka, Kevin Truskowski, Asmita Nandi, Gloria E. Marino-Bravante, Alexis E. Carey, Naina Gour, Devon A. Maranto, Murilo R. Rocha, Elizabeth I. Harper, Justin Ruiz, Evan J. Lipson, Elizabeth M. Jaffee, Kristin Bibee, Joel C. Sunshine, and Hongkai Ji from Johns Hopkins; Mitchell E. Fane from Fox Chase Cancer Center in Philadelphia; and Laura Hüser from Johnson & Johnson. Fane and Hüser were associated with Johns Hopkins at the time of the study.
This research and its authors were supported partly by Johns Hopkins, the National Cancer Institute (grants P30CA00697356, P01CA114046, U01CA227550, R01CA232256, and R01CA207935), the National Institutes of Health (grant 5T32CA009071-40), the Howard Hughes Medical Institute, the Conquer Cancer Foundation Young Investigator Award, the Cholangiocarcinoma Foundation Research Fellowship, the MD Anderson GI SPORE Career Enhancement Program, a Maryland Cancer Moonshot Grant awarded to Johns Hopkins, and the Dermatology Foundation. Ji and Zhao received support from Deutsche Forschungsgemeinschaft (DFG) and a Team Science Award from the Melanoma Research Alliance.
Weeraratna is a board member of reGAIN Therapeutics. Jaffee has reported receiving grants, support, or fees from various organizations, including Abmeta, Genocea, Achilles, DragonFly, Candel Therapeutics, the Parker Institute, Lustgarten, Genentech, AstraZeneca, and Break Through Cancer. Johns Hopkins has also received grants from Roche/Genentech on behalf of Zabransky. These relationships are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
