Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility

Edna Cukierman, Amanpreet Kaur, Brett L. Ecker, Stephen M. Douglass, Curtis H. Kugel, Marie R. Webster, Filipe Almeida, Rajasekharan Somasundaram, James Hayden, Ehsan Ban, Hossein Ahmadzadeh, Janusz Franco-Barraza, Neelima Shah, Ian A. Mellis, Frederick Keeney, Andrew Kossenkov, Hsin Yao Tang, Xiangfan Yin, Qin Liu, Xiaowei XuMitchell Fane, Patricia Brafford, Meenhard Herlyn, David W. Speicher, Jennifer A. Wargo, Michael T. Tetzlaff, Lauren E. Haydu, Arjun Raj, V. B. Shenoy, Ashani T. Weeraratna

Research output: Contribution to journalArticlepeer-review

271 Scopus citations

Abstract

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. See related commentary by Marie and Merlino, p. 19. This article is highlighted in the In This Issue feature, p. 1.

Original languageEnglish
Pages (from-to)64-81
Number of pages18
JournalCancer Discovery
Volume9
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • Aging
  • Animals
  • Cells, Cultured
  • Collagen/metabolism
  • Extracellular Matrix Proteins/metabolism
  • Fibroblasts/metabolism
  • Humans
  • Immune System
  • Melanoma/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Proteoglycans/metabolism
  • Skin/metabolism
  • Tumor Microenvironment

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