Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration
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Vida Farsam1,*, Abhijit Basu1,*, Martina Gatzka1, Nicolai Treiber1, Lars A. Schneider1, Medhanie A. Mulaw2, Tanja Lucas3, Stefan Kochanek3, Reinhard Dummer4, Mitchell P. Levesque4, Meinhard Wlaschek1, Karin Scharffetter-Kochanek1
1Department of Dermatology and Allergic Diseases, University of Ulm, Germany
2Institute of Experimental Cancer Research, University of Ulm, Germany
3Department of Gene Therapy, University of Ulm, Germany
4Department of Dermatology, University Hospital Zurich, Switzerland
*These authors contributed equally to this work
Karin Scharffetter-Kochanek, email: firstname.lastname@example.org
Keywords: cutaneous squamous cell carcinoma (cSCC), senescence-associated secretory phenotype (SASP), tumor migration, Chemerin, chemokine CC-motif receptor-like 2 (CCRL2)
Received: May 09, 2016 Accepted: October 21, 2016 Published: November 18, 2016
Aging is associated with a rising incidence of cutaneous squamous cell carcinoma (cSCC), an aggressive skin cancer with the potential for local invasion and metastasis. Acquisition of a senescence-associated secretory phenotype (SASP) in dermal fibroblasts has been postulated to promote skin cancer progression in elderly individuals. The underlying molecular mechanisms are largely unexplored. We show that Chemerin, a previously unreported SASP factor released from senescent human dermal fibroblasts, promotes cSCC cell migration, a key feature driving tumor progression. Whereas the Chemerin abundance is downregulated in malignant cSCC cells, increased Chemerin transcripts and protein concentrations are detected in replicative senescent fibroblasts in vitro and in the fibroblast of skin sections from old donors, indicating that a Chemerin gradient is built up in the dermis of elderly. Using Transwell® migration assays, we show that Chemerin enhances the chemotaxis of different cSCC cell lines. Notably, the Chemerin receptor CCRL2 is remarkably upregulated in cSCC cell lines and human patient biopsies. Silencing Chemerin in senescent fibroblasts or the CCRL2 and GPR1 receptors in the SCL-1 cSCC cell line abrogates the Chemerin-mediated chemotaxis. Chemerin triggers the MAPK cascade via JNK and ERK1 activation, whereby the inhibition impairs the SASP- or Chemerin-mediated cSCC cell migration.
Taken together, we uncover a key role for Chemerin, as a major factor in the secretome of senescent fibroblasts, promoting cSCC cell migration and possibly progression, relaying its signals through CCRL2 and GPR1 receptors with subsequent MAPK activation. These findings might have implications for targeted therapeutic interventions in elderly patients.
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