Recurrence and Resistance in the Aging Melanoma Microenvironment

Metastatic recurrence in melanoma patients often occurs when dormant tumor cells at distant sites reawaken, even after seemingly successful initial treatment. This process of tumor dormancy, where disseminated tumor cells remain inactive before eventual reactivation, remains poorly understood despite its clinical significance. Notably, aging emerges as a critical factor in poor melanoma prognosis, suggesting that age-related changes in the tissue environment may influence both tumor dormancy and therapeutic resistance. Our research has revealed that aged lung fibroblasts significantly impact how melanoma cells emerge from dormancy through complex Wnt signaling pathways. Recent findings demonstrate a crucial switch between non-canonical and canonical Wnt signaling that appears to control entry into and exit from tumor dormancy. Additionally, we have discovered that host factors, including sex, influence age-related metastatic spread and treatment response. Particularly intriguing is our observation that aged fibroblasts, unlike their younger counterparts, show unique responses to the presence of cancer cells, even at distant sites. These aged fibroblasts increase their proliferation and secrete factors that create an immunosuppressive environment by recruiting myeloid-derived suppressor cells. This immune-suppressed environment may then permit the growth of rapidly proliferating cells that would typically be eliminated by immune surveillance. The relationship between dormancy and therapy resistance presents another critical aspect of this research. While Wnt5A drives resistance to targeted therapy through a senescence-like state, canonical Wnt signaling typically increases sensitivity to BRAF/MEK inhibitors. Understanding how these opposing pathways interact, particularly in the context of aging, may reveal new therapeutic opportunities. This research aims to uncover how the aging immune microenvironment influences tumor cell dormancy and subsequent recurrence. By investigating the complex interplay between stromal cells, immune components, and Wnt signaling pathways, we hope to identify new therapeutic strategies to prevent metastatic recurrence in aging melanoma patients. These findings could lead to more effective treatments that consider both the age of the patient and the dynamic nature of tumor dormancy.