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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 X , Liu Q , Xu X , 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. 2018 Oct 2;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 3D skin reconstruction models, and in vivo. Intriguingly, aged fibroblast-derived matrices had the opposite effects 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 Treg recruitment. These data suggest while age-related physical changes in the ECM can promote tumor cell motility, they may adversely impact 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 melanoma patients.
2159-8290 Kaur, Amanpreet ORCID: https://orcid.org/0000-0002-4228-2742 Ecker, Brett L Douglass, Stephen M Kugel, Curtis H Webster, Marie R Almeida, Filipe V Somasundaram, Rajasekharan Hayden, James Ban, Ehsan Ahmadzadeh, Hossein Franco-Barraza, Janusz ORCID: https://orcid.org/0000-0003-3652-5311 Shah, Neelima Mellis, Ian A ORCID: https://orcid.org/0000-0002-6239-4821 Keeney, Frederick Kossenkov, Andrew Tang, Hsin-Yao ORCID: https://orcid.org/0000-0003-1838-018X Yin, Xiangfan Liu, Qin ORCID: https://orcid.org/0000-0001-9964-580X Xu, Xiaowei Fane, Mitchell ORCID: https://orcid.org/0000-0001-6163-5753 Brafford, Patricia Herlyn, Meenhard Speicher, David W Wargo, Jennifer A Tetzlaff, Michael T Haydu, Lauren E Raj, Arjun ORCID: https://orcid.org/0000-0002-2915-6960 Shenoy, Vivek Cukierman, Edna ORCID: https://orcid.org/0000-0002-1452-9576 Weeraratna, Ashani T R01 CA113451/CA/NCI NIH HHS/United States R01 CA174746/CA/NCI NIH HHS/United States R01 CA207935/CA/NCI NIH HHS/United States U01 CA227550/CA/NCI NIH HHS/United States Journal Article United States Cancer Discov. 2018 Oct 2. pii: 2159-8290.CD-18-0193. doi: 10.1158/2159-8290.CD-18-0193.