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Kaur A , Ecker BL , Douglass SM , Kugel CH , Webster MR , Almeida FV , Somasundaram R , Hayden J , Ban E , Ahmadzadeh H , Franco-Barraza J , Shah N , Mellis IA , Keeney F , Kossenkov A , Tang HY , Yin XF , Liu Q , Xu XW , Fane M , Brafford P , Herlyn M , Speicher DW , Wargo JA , Tetzlaff MT , Haydu LE , Raj A , Shenoy V , Cukierman E , Weeraratna AT
Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility
Cancer Discov. 2019 Jan;9(1) :64-81
PMID: 30279173    PMCID: PMC6328333    URL: https://www.ncbi.nlm.nih.gov/pubmed/30279173
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Physical changes in skin are among the most visible signs of aging. We found that young dermal fibroblasts secrete high levels of extracellular matrix (ECM) constituents, including proteoglycans, glycoproteins, and cartilage-linking proteins. The most abundantly secreted was HAPLN1, a hyaluronic and proteoglycan link protein. HAPLN1 was lost in aged fibroblasts, resulting in a more aligned ECM that promoted metastasis of melanoma cells. Reconstituting HAPLN1 inhibited metastasis in an aged microenvironment, in 3-D skin reconstruction models, and in vivo. Intriguingly, aged fibroblast-derived matrices had the opposite effect on the migration of T cells, inhibiting their motility. HAPLN1 treatment of aged fibroblasts restored motility of mononuclear immune cells, while impeding that of polymorphonuclear immune cells, which in turn affected regulatory T-cell recruitment. These data suggest that although age-related physical changes in the ECM can promote tumor cell motility, they may adversely affect the motility of some immune cells, resulting in an overall change in the immune microenvironment. Understanding the physical changes in aging skin may provide avenues for more effective therapy for older patients with melanoma. SIGNIFICANCE: These data shed light on the mechanochemical interactions that occur between aged skin, tumor, and immune cell populations, which may affect tumor metastasis and immune cell infiltration, with implications for the efficacy of current therapies for melanoma.
Kaur, Amanpreet Ecker, Brett L. Douglass, Stephen M. Kugel, Curtis H., III Webster, Marie R. Almeida, Filipe, V Somasundaram, Rajasekharan Hayden, James Ban, Ehsan Ahmadzadeh, Hossein Franco-Barraza, Janusz Shah, Neelima Mellis, Ian A. Keeney, Frederick Kossenkov, Andrew Tang, Hsin-Yao Yin, Xiangfan Liu, Qin Xu, Xiaowei Fane, Mitchell Brafford, Patricia Herlyn, Meenhard Speicher, David W. Wargo, Jennifer A. Tetzlaff, Michael T. Haydu, Lauren E. Raj, Arjun Shenoy, Vivek Cukierman, Edna Weeraratna, Ashani T. , Amanpreet/0000-0002-4228-2742 2159-8290 K99 CA208012/CA/NCI NIH HHS/ R01 CA113451/CA/NCI NIH HHS/ P30 CA010815/CA/NCI NIH HHS/ P01 CA114046/CA/NCI NIH HHS/ R01 CA174746/CA/NCI NIH HHS/ P50 CA174523/CA/NCI NIH HHS/ R01 CA207935/CA/NCI NIH HHS/ F99 CA212437/CA/NCI NIH HHS/ R01 CA131582/CA/NCI NIH HHS/ T32 CA009171/CA/NCI NIH HHS/ U01 CA227550/CA/NCI NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ Cancer Discov. 2019 Jan;9(1):64-81. doi: 10.1158/2159-8290.CD-18-0193. Epub 2018 Oct 2.