title: IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin.
abstract: Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b-/- mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin-a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas.
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Denada
authors.initials: D
authors.lastname: Dibra
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Abhisek
authors.initials: A
authors.lastname: Mitra
authors.affiliation: Banfield Pet Hospital, Sugar Land, TX 77479, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Newman
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.affiliation: The University of Texas Health Science Center at Houston, Medical School, Houston, TX 77030, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Keenan
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jeffry J
authors.initials: JJ
authors.lastname: Cutrera
authors.affiliation: Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Mathis
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Myers
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics* / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics; D018123:Receptors, Interleukin; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055153:Stem Cell Niche
chemical_list: D039481:CD11b Antigen; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D007378:Interleukins; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; C511404:ZD4054; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ET1/ETAR; IL27; IL27RA; KRAS; inflammation