Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis

Brett L. Ecker, Amanpreet Kaur, Stephen M. Douglass, Marie R. Webster, Filipe V. Almeida, Gloria E. Marino, Andrew J. Sinnamon, Madalyn G. Neuwirth, Gretchen M. Alicea, Abibatou Ndoye, Mitchell Fane, Xiaowei Xu, Myung Shin Sim, Gary B. Deutsch, Mark B. Faries, Giorgos C. Karakousis, Ashani T. Weeraratna

Research output: Contribution to journalArticle

Abstract

Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inabil-ity to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics. SIGNIFICANCE: Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)82-95
Number of pages14
JournalCancer discovery
Volume9
Issue number1
DOIs
StatePublished - Jan 2019
Externally publishedYes

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Extracellular Matrix
Melanoma
Permeability
Neoplasm Metastasis
Technetium
Survival
Fibroblasts
Sentinel Lymph Node Biopsy
Tumor Microenvironment
Dermis
Neoplasms
Lymph Nodes

ASJC Scopus subject areas

  • Oncology

Cite this

Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. / Ecker, Brett L.; Kaur, Amanpreet; Douglass, Stephen M.; Webster, Marie R.; Almeida, Filipe V.; Marino, Gloria E.; Sinnamon, Andrew J.; Neuwirth, Madalyn G.; Alicea, Gretchen M.; Ndoye, Abibatou; Fane, Mitchell; Xu, Xiaowei; Sim, Myung Shin; Deutsch, Gary B.; Faries, Mark B.; Karakousis, Giorgos C.; Weeraratna, Ashani T.

In: Cancer discovery, Vol. 9, No. 1, 01.2019, p. 82-95.

Research output: Contribution to journalArticle

Ecker, BL, Kaur, A, Douglass, SM, Webster, MR, Almeida, FV, Marino, GE, Sinnamon, AJ, Neuwirth, MG, Alicea, GM, Ndoye, A, Fane, M, Xu, X, Sim, MS, Deutsch, GB, Faries, MB, Karakousis, GC & Weeraratna, AT 2019, 'Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis', Cancer discovery, vol. 9, no. 1, pp. 82-95. https://doi.org/10.1158/2159-8290.CD-18-0168
Ecker, Brett L. ; Kaur, Amanpreet ; Douglass, Stephen M. ; Webster, Marie R. ; Almeida, Filipe V. ; Marino, Gloria E. ; Sinnamon, Andrew J. ; Neuwirth, Madalyn G. ; Alicea, Gretchen M. ; Ndoye, Abibatou ; Fane, Mitchell ; Xu, Xiaowei ; Sim, Myung Shin ; Deutsch, Gary B. ; Faries, Mark B. ; Karakousis, Giorgos C. ; Weeraratna, Ashani T. / Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. In: Cancer discovery. 2019 ; Vol. 9, No. 1. pp. 82-95.
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abstract = "Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inabil-ity to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics. SIGNIFICANCE: Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment.",
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AU - Kaur, Amanpreet

AU - Douglass, Stephen M.

AU - Webster, Marie R.

AU - Almeida, Filipe V.

AU - Marino, Gloria E.

AU - Sinnamon, Andrew J.

AU - Neuwirth, Madalyn G.

AU - Alicea, Gretchen M.

AU - Ndoye, Abibatou

AU - Fane, Mitchell

AU - Xu, Xiaowei

AU - Sim, Myung Shin

AU - Deutsch, Gary B.

AU - Faries, Mark B.

AU - Karakousis, Giorgos C.

AU - Weeraratna, Ashani T.

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N2 - Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inabil-ity to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics. SIGNIFICANCE: Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment.

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