title: Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration.
abstract: 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.
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Germany.
authors.forename: Vida
authors.initials: V
authors.lastname: Farsam
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Germany.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Basu
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Gatzka
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Treiber
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Germany.
authors.forename: Lars A
authors.initials: LA
authors.lastname: Schneider
authors.affiliation: Institute of Experimental Cancer Research, University of Ulm, Germany.
authors.forename: Medhanie A
authors.initials: MA
authors.lastname: Mulaw
authors.affiliation: Department of Gene Therapy, University of Ulm, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Lucas
authors.affiliation: Department of Gene Therapy, University of Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
authors.affiliation: Department of Dermatology, University Hospital Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Dermatology, University Hospital Zurich, Switzerland.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Germany.
authors.forename: Meinhard
authors.initials: M
authors.lastname: Wlaschek
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
mesh_terms: D000369:Aged, 80 and over; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D018920:Coculture Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D034622:RNA Interference; D054388:Receptors, CCR / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: C487531:CCRL2 protein, human; D018925:Chemokines; C504821:GPR1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D054388:Receptors, CCR; D043562:Receptors, G-Protein-Coupled; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3
keywords: Chemerin; chemokine CC-motif receptor-like 2 (CCRL2); cutaneous squamous cell carcinoma (cSCC); senescence-associated secretory phenotype (SASP); tumor migration