Stromal changes in the aged lung induce an emergence from melanoma dormancy

Abstract

Dormant tumor cells escape the primary site, do not grow out into macroscopic tumors in the distal site, but maintain enough plasticity to reactivate and form overt metastatic lesions, sometimes taking several decades. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for e cient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state 1-3 . Dermal broblasts are key orchestrators of promoting phenotype switching in melanoma via changes in the secretion of soluble factors during aging [4][5][6][7][8] . Speci cally, we have identi ed Wnt5A as a master regulator of activating metastatic dormancy, which enables e cient seeding and survival of melanoma cells in metastatic niches. Age-induced reprogramming of lung broblasts increases their secretion of the soluble Wnt antagonist sFRP1, which inhibits Wnt5A, enabling e cient metastatic outgrowth. Further, we have identi ed the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis respectively. Overall, we nd that age-induced changes in distal metastatic microenvironments promotes e cient reactivation of dormant melanoma cells in the lung. MainWe have previously established that melanoma cells implanted in aged mouse skin metastasize to the lung at greater rates than in younger animals 4 . Whether this is due to increased dissemination from the primary site, or because the aged microenvironment at metastatic sites promotes outgrowth remained unclear. To investigate this, we intradermally implanted Yumm1.7 (mCherry) melanoma cells into young (8 weeks) and aged (> 52 weeks) C57BL6 mice. The primary tumor in the skin grew faster in young mice (Fig. 1A). We examined distal lung metastases at weeks 1, 3 and 5 using immunohistochemical (IHC) analysis of mCherry positive cells in the lung. At week 1, we failed to detect melanoma cells. At week 3, we found that melanoma cells e ciently seed the lung in equal numbers in young and aged mice (Fig. 1B) as single cell colonies (Fig. 1C, top panels); however, at week 5, larger metastatic colonies formed in the aged lung (Fig. 1C, bottom right), while cells persisted as single cells in the young (Fig. 1C, bottom left). While the number of cells that seeded in the young vs. aged lung are similar, the rate at which cells seed the lung (no. of cells disseminating/mm 3 of tumor volume) was far lower in young mice. Thus, to determine whether the difference in lung outgrowth at week 5 was due to an overall increase in dissemination from aged primary tumors, we removed the primary tumors from aged m...

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

“…The receptor tyrosine kinase AXL has also been implicated in breast cancer progression and metastasis ( 68, 69 ), making it an attractive target in clinical settings. AXL is upregulated in bone dormant myeloma cells ( 202 ), and its overexpression reduces the number of Ki67-positive lung DTCs in melanoma ( 203 ). Intriguingly, this role is not universal between cancer lineages, as depleting AXL in HER2 + DTCs after extravasation reduced metastatic burden ( 68 ).…”

The glutathione S-transferase Gstt1 is a robust driver of survival and dissemination in metastases

“…Extracellular matrix (ECM) proteins, such as Fibronectin have been shown to be integral to the maintenance of a supportive metastatic niche ( 7,13,34,43 ). However, these studies have focused solely on the extracellular deposition of Fibronectin fibrils as critical for maintenance of metastatic phenotypes.…”

“…Metastatic colonization, growth and maintenance are strongly influenced by cues from the metastatic tumor microenvironment ( 1, 13, 21, 34, 36, 41, 44 ) and recent studies have laid the groundwork for targeting the ECM as a mechanism for sensitizing slow growing disseminated tumor cells to chemotherapy ( 7,13,16,34,43 ). Our work identifies a novel, subpopulation of slow cycling Gstt1 high /CK19 low metastatic cells which express intracellular Fibronectin to promote metastasis.…”

Noncanonical Wnt/Ror2 signaling regulates cell–matrix adhesion to prompt directional tumor cell invasion in breast cancer

“…, 2021 ), and factors like cellular heterogeneity, receptor/ligand context, cellular cross-talk, and the multistep nature of cancer metastasis likely contribute to the complexity of the Wnt signaling function in cancer, much like TGF-β and its known pleiotropic functions ( Bierie and Moses, 2006 ). For instance, in melanoma, changes in cell and microenvironment contexts are integral in shaping different cellular phenotypes dictated by Wnt5a, a key ligand for Ror2, in primary and metastatic settings ( Fane et al. , 2022 ).…”