TY - JOUR
T1 - Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility
AU - Kaur, Amanpreet
AU - Ecker, Brett L.
AU - Douglass, Stephen M.
AU - Kugel, Curtis H.
AU - Webster, Marie R.
AU - Almeida, Filipe V.
AU - Somasundaram, Rajasekharan
AU - Hayden, James
AU - Ban, Ehsan
AU - Ahmadzadeh, Hossein
AU - Franco-Barraza, Janusz
AU - Shah, Neelima
AU - Mellis, Ian A.
AU - Keeney, Frederick
AU - Kossenkov, Andrew
AU - Tang, Hsin Yao
AU - Yin, Xiangfan
AU - Liu, Qin
AU - Xu, Xiaowei
AU - Fane, Mitchell
AU - Brafford, Patricia
AU - Herlyn, Meenhard
AU - Speicher, David W.
AU - Wargo, Jennifer A.
AU - Tetzlaff, Michael T.
AU - Haydu, Lauren E.
AU - Raj, Arjun
AU - Shenoy, Vivek
AU - Cukierman, Edna
AU - Weeraratna, Ashani T.
N1 - Funding Information:
We thank Dr. Katie Marchbank for technical assistance with the preparation of fibroblasts for proteomics and Dr. Chi Van Dang for critical reading of the manuscript. NIH funding (NCI): We thank the outstanding Core Facilities of the Wistar Institute supported by P30CA010815; A.T. Weeraratna, S.M. Douglass, and Q. Liu are supported by R01CA174746 and R01CA207935. A. Kaur is supported by F99CA212437. X. Xu, X. Yin, Q. Liu, M. Herlyn, D.W. Speicher, M. Fane, and A.T. Weeraratna are also supported by P01 CA114046 and P50CA174523. C.H. Kugel III is supported by T32CA009171. M.R. Webster is supported by K99CA208012. D.W. Speicher is supported by RO1CA131582. E. Cukierman is supported by R01 CA113451 and P30CA06927. Other funding: A.T. Weeraratna is also supported by the Melanoma Research Fund, Melanoma Research Alliance/L’Oréal Paris-USA Women in Science Team Science Award, the Ira Brind Endowment, and the Wistar Science Discovery Fund. M. Herlyn is supported by a gift from the Adelson Medical Research Foundation. E. Cukierman is supported by DODW81XH-15-1-0170 and a gift from Mrs. Con-cetta Greenberg in memory of Dr. Marvin Greenberg. V. Shenoy is supported by the NSF Center for Engineering Mechanobiology (CMMI-154857).
Funding Information:
We thank Dr. Katie Marchbank for technical assistance with the preparation of fibroblasts for proteomics and Dr. Chi Van Dang for critical reading of the manuscript. NIH funding (NCI): We thank the outstanding Core Facilities of the Wistar Institute supported by P30CA010815; A.T. Weeraratna, S.M. Douglass, and Q. Liu are supported by R01CA174746 and R01CA207935. A. Kaur is supported by F99CA212437. X. Xu, X. Yin, Q. Liu, M. Herlyn, D.W. Speicher, M. Fane, and A.T. Weeraratna are also supported by P01 CA114046 and P50CA174523. C.H. Kugel III is supported by T32CA009171. M.R. Webster is supported by K99CA208012. D.W. Speicher is supported by RO1CA131582. E. Cukierman is supported by R01 CA113451 and P30CA06927. Other funding: A.T. Weeraratna is also supported by the Melanoma Research Fund, Melanoma Research Alliance/L’Oréal Paris-USA Women in Science Team Science Award, the Ira Brind Endowment, and the Wistar Science Discovery Fund. M. Herlyn is supported by a gift from the Adelson Medical Research Foundation. E. Cukierman is supported by DODW81XH-15-1-0170 and a gift from Mrs. Concetta Greenberg in memory of Dr. Marvin Greenberg. V. Shenoy is supported by the NSF Center for Engineering Mechanobiology (CMMI-154857).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/1
Y1 - 2019/1
N2 - 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) con-stituents, 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 mononu-clear 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.
AB - 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) con-stituents, 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 mononu-clear 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85056124921&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-18-0193
DO - 10.1158/2159-8290.CD-18-0193
M3 - Article
C2 - 30279173
AN - SCOPUS:85056124921
VL - 9
SP - 64
EP - 81
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 1
ER -