IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin

Denada Dibra, Abhisek Mitra, Melissa Newman, Xueqing Xia, Camille Keenan, Jeffry J. Cutrera, James Michael Mathis, Xiao Jing Wang, Jeffrey Myers, Shulin Li

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)77138-77151
Number of pages14
JournalOncotarget
Volume7
Issue number47
DOIs
StatePublished - 1 Jan 2016

Fingerprint

Interleukin-27
Endothelin A Receptors
Carcinogenesis
Skin
Neoplasms
Papilloma
Bone Marrow Cells
Squamous Cell Carcinoma
Anti-Inflammatory Agents
Stem Cells
Cytokines
Incidence
Research

Keywords

  • ET1/ETAR
  • IL27
  • IL27RA
  • Inflammation
  • KRAS

Cite this

Dibra, D., Mitra, A., Newman, M., Xia, X., Keenan, C., Cutrera, J. J., ... Li, S. (2016). IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin. Oncotarget, 7(47), 77138-77151. https://doi.org/10.18632/oncotarget.12581
Dibra, Denada ; Mitra, Abhisek ; Newman, Melissa ; Xia, Xueqing ; Keenan, Camille ; Cutrera, Jeffry J. ; Mathis, James Michael ; Wang, Xiao Jing ; Myers, Jeffrey ; Li, Shulin. / IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin. In: Oncotarget. 2016 ; Vol. 7, No. 47. pp. 77138-77151.
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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.",
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Dibra, D, Mitra, A, Newman, M, Xia, X, Keenan, C, Cutrera, JJ, Mathis, JM, Wang, XJ, Myers, J & Li, S 2016, 'IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin', Oncotarget, vol. 7, no. 47, pp. 77138-77151. https://doi.org/10.18632/oncotarget.12581

IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin. / Dibra, Denada; Mitra, Abhisek; Newman, Melissa; Xia, Xueqing; Keenan, Camille; Cutrera, Jeffry J.; Mathis, James Michael; Wang, Xiao Jing; Myers, Jeffrey; Li, Shulin.

In: Oncotarget, Vol. 7, No. 47, 01.01.2016, p. 77138-77151.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Dibra, Denada

AU - Mitra, Abhisek

AU - Newman, Melissa

AU - Xia, Xueqing

AU - Keenan, Camille

AU - Cutrera, Jeffry J.

AU - Mathis, James Michael

AU - Wang, Xiao Jing

AU - Myers, Jeffrey

AU - Li, Shulin

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