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Soo Park, MD
Soo Park, MD
Posted: Monday, October 21, 2024
Yash Chhabra, PhD, of Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues observed that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. Additionally, aged male skin fibroblasts appeared to selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Thus, the investigators suggest that specific treatments such as neutralization antibodies or antagonists that block BMP2 activity in the tumor cells may make them less invasive and more sensitive to anticancer therapies. These findings were published in Cell.
“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 Dr. Chhabra in a Fox Chase press release.
The study used human primary dermal fibroblasts isolated from non–sun-exposed skin of healthy donors as part of the Baltimore Longitudinal Study of Aging. The investigators stratified them as young (< 35 years) or older (> 55 years) and male or female based on fibroblast karyotyping. Melanoma tumor cells were transplanted into aged mice.
The researchers found more DNA damage accumulated in cells transplanted in aged male mice, regardless of genetic differences. These tumors in aged male mice were more metastatic and resistant to targeted therapy. This finding suggests that host factors, such as age and biologic sex, may differentially impact how cancer cells grow, spread, and respond to treatments.
When aged human male and female fibroblasts were compared, higher levels of BMP2 were found to be secreted by aged male fibroblasts. Researchers showed how an increase in local BMP2 in the tumor microenvironment caused melanoma cells to become more invasive and resistant to targeted anticancer therapies.
Disclosure: For full disclosures of the study authors, visit www.cell.com.
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