Aged Lungs Enable Metastatic Outgrowth of Dormant Melanoma Cells

Tumor dormancy describes the phenomenon in which cancer cells disseminate from a primary tumor to distant sites, remaining in a nonproliferative dormant state for up to many years before forming overt metastases. Although clinical management of melanoma has been greatly improved by immunotherapy and targeted therapy, metastatic relapse is common, while mechanisms regulating melanoma tumor dormancy and metastatic reactivation are not fully understood. To address this, Fane and colleagues studied a metastasis model in which murine melanoma cells were intradermally transplanted into young (8 weeks) or aged (over 52 weeks) mice, demonstrating that despite similar rates of dissemination proliferative overt metastases occurred only in the lungs of aged mice. Coculture assays suggested that aged murine lung fibroblasts generate a permissive microenvironment for metastatic outgrowth. Moreover, proteomic analysis indicated that aged fibroblasts had significantly higher levels of secreted frizzled related protein 1 (SFRP1), a noncanonical WNT antagonist, and administration of an anti-SFRP1 neutralizing antibody abrogated metastatic outgrowth in aged mice, suggesting the importance of WNT signaling in sustaining a dormant metastatic phenotype. Given studies establishing the role of WNT5A in promoting prostate tumor dormancy, clinical melanoma samples from The Cancer Genome Atlas were stratified based on WNT5A expression, revealing that high WNT5A expression in melanoma was associated with high expression of dormancy markers and low expression of proliferative markers. Genetic knockdown of Wnt5a following initial cancer cell dissemination was sufficient to form overt metastases in young mice, whereas forced overexpression of Wnt5a after dissemination prevented overt metastases in previously permissive aged mice, supporting that the aged lung microenvironment shifts cancer cells from high to low WNT5A signaling and promotes the transition from dormancy to reactivation. In addition, reactivation was triggered, in part, through inverse expression of the receptor tyrosine kinases AXL and MER, in which the shift to overt metastatic growth in the lung required low AXL and high MER expression. Together, this work elucidates a mechanism by which a metastatic microenvironment undergoes changes that reawaken dormant cancer cells.

Fane ME, Chhabra Y, Alicea GM, Maranto DA, Douglass SM, Webster MR, et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 2022;606:396–405.

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