Aged Tumor Microenvironment Promotes Elevated Autophagy in Cutaneous Melanoma

Embargo until
2026-12-01
Date
2022-12-16
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
Deadliest of all skin cancers, melanoma is highly metastatic and markedly resistant to modern therapies. Age-adjusted incidence rates of melanoma have risen 1.2% each year over the last decade, whereas death rates have decreased 3.3% each year in that same time. While these statistics highlight broad improvements in treatment, age-stratification reveals that older patients bear a disproportionately greater cancer burden. In striving to elucidate the complex relationship between aging and therapy resistance, there has been a growing appreciation for the role of the tumor microenvironment (TME) in tumorigenesis. With age, the TME undergoes biophysical, chemical, and immunological changes that confer a therapeutically resistant phenotype. As age is a predictor of survival, understanding the age-related changes in the TME has the potential to equitably improve therapy outcomes for older patient populations. Although various signaling pathways involved in melanoma therapy resistance have been well studied, cellular features driving resistance have received little attention. A hallmark of both cancer and aging, compromised autophagy describes a highly evolutionarily conserved, intracellular pathway responsible for the clearance of cytosolic waste via lysosomal degradation. Although autophagy is responsible for the basal turnover of molecular and cellular components, it can also be induced by various physiologic and pathologic stresses, including cancer. In melanoma, recent studies have demonstrated an upregulation of autophagic activity wherein tumor cells hijack cellular machinery to meet increased metabolic demands. As a prominent regulator of the TME, autophagy is a unique target for cancer intervention. However, the interconnected relationship between autophagy, age, and the TME is not well understood. Therefore, this study sought to characterize autophagy in young and aged dermal fibroblast and cutaneous melanoma cell lines. These data revealed elevated autophagy in the aged melanoma TME with possible origins in endoplasmic reticulum and oxidative stress pathways. Further, while the aged TME demonstrated greater autophagy, it resolved physiologic stress less efficiently, as indicated by measures of autophagic flux. Thus, therapies that inhibit autophagy may be especially effective in aged cancer patients. Future investigation of age-related changes within the TME is recommended to improve patient outcomes and reduce the societal burden of cancer at large.
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Keywords
Melanoma, Tumor Microenvironment, Aging, Autophagy, Dermal Fibroblasts
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