Study From Researchers at Fox Chase Cancer Center and Johns Hopkins Kimmel Cancer Center Shows Aged Male Fibroblasts Increase Melanoma Treatment Resistance

In a study published today in the prestigious journal Cell, researchers from Fox Chase Cancer Center and Johns Hopkins Kimmel Cancer Center showed changes that occur with age in male skin fibroblasts contributed to an increase in the spread of melanoma cells and made cancer cells resistant to targeted therapy. 

Fibroblasts are a type of cell that are most common in connective tissue and are essential to wound healing and tissue maintenance. In cases of melanoma, a potentially deadly skin cancer, men are more at risk than women and tend to develop more aggressive, hard-to-treat melanomas, particularly at advanced ages.

“What we wanted to do is combine both the variables of age and biological sex and ask what local tumor microenvironment changes are happening across males and females with advancing age that can answer questions about differences in metastasis and treatment response between patients,” said Yash Chhabra, PhD, lead author on the study and Assistant Professor in the Cancer Signaling and Microenvironment Research Program at Fox Chase. The melanoma tumor microenvironment consists of the fibroblasts in the immediate vicinity of cancer cells that play a key role in the growth of tumors. 

Chhabra completed the research for the study while at Johns Hopkins Bloomberg School of Public Health, where he worked alongside Ashani T. Weeraratna, PhD, Bloomberg Distinguished Professor and E.V. McCollum Chair of the Department of Biochemistry and Molecular Biology at the Johns Hopkins Bloomberg School of Public Health. Weeraratna is also Associate Director for Laboratory Research at the Johns Hopkins Sidney Kimmel Cancer Center.

“A lot of studies in the past have combined the sexes into the same pool, so differences tend to get diluted,” said Chhabra. “By first carefully stratifying fibroblast samples based on the host sex and age, we could focus on the differences within these fibroblasts and have a better understanding of how those differences play a role in melanoma metastasis and treatment response.”

To evaluate how these differences affect the tumor microenvironment, researchers transplanted melanoma tumor cells into aged male or female mice. They found more DNA damage accumulated in cells transplanted in the aged male mice, regardless of the genetic differences. These tumors in aged male mice were more metastatic and resistant to targeted therapy, which suggested that host factors such as age and biological sex can differentially impact how cancer cells grow, spread, and respond to treatments.

By comparing the aged human male and female fibroblasts, Chhabra, Weeraratna, and their colleagues found higher levels of bone morphogenic protein 2 (BMP2), a protein usually involved in the development of bone and cartilage, secreted by aged male fibroblasts. They showed how an increase in local BMP2 in the tumor microenvironment caused melanoma cells to become more invasive and resistant to targeted anticancer therapies, suggesting that the aging that occurs in male fibroblasts contributes to more aggressive melanomas that are harder to treat.

In the study published today, the researchers found that using specific treatments such as neutralization antibodies or antagonists that block BMP2 activity in the tumor cells makes them less invasive and more sensitive to anticancer therapies.

Weeraratna said the results show that studying cancer in older mice and utilizing aging human cells is essential, as the same therapy may not work in all patients. “We also need to understand whether men and women respond differently to therapies and better tailor their therapy to both sex- and age-related differences,” she said.

“There are numerous factors and processes that change with age, and next we want to look at some of these differences at the immune level,” added Chhabra, “because it’s well known that the male and female immune systems elicit different responses to self and foreign antigens. This study was mainly looking at targeted therapy, and now we want to proceed with studying differences in patient responses to immune checkpoint therapy, which is standard of care in melanoma patients.”

The study is titled “Sex-Dependent Effects in the Aged Melanoma Tumor Microenvironment Influences Invasion and Resistance to Targeted Therapy.”