Impact of age-related dermal microenvironment on keratinocyte skin cancer development

Summary: Abstract Body: Keratinocyte skin cancer is common among the elderly, yet the underlying mechanisms driving its development remain poorly understood. Dermal fibroblasts in aged human skin express increased levels of CCN1 (Cell Communication Network family member 1), a multifunctional protein that regulates the homeostasis of the dermal extracellular matrix (ECM). Mice that express CCN1 (Col1a2-CCN1 mice) in dermal fibroblasts exhibit pronounced features of dermal aging, including fragmentation and disorganization of the collagenous ECM and a proinflammatory dermal microenvironment. Given that aging is a significant risk factor for keratinocyte cancers, we have investigated the influence of the age-related dermal microenvironment on keratinocyte skin cancer development in Col1a2-CCN1 mice, compared to matched littermate control mice. At six months of age, Col1a2-CCN1 mice demonstrate significantly increased keratinocyte cancer development in two different cancer models: transformed keratinocyte xenograft (N=5, P<0.001) and oncogenic HRas expression in keratinocytes (N=5, p<0.01). RNA-seq analysis of Col1a2-CCN1 mice skin identified substantial enrichments of cancer-related pathways, particularly hepatocyte growth factor (HGF) signaling. Importantly, inhibition of HGF signaling in Col1a2-CCN1 mice, with c-Met inhibitor PHA665752, substantially blocked tumor development following two-stage chemical carcinogenesis (N=4, p<0.01) or oncogenic HRas expression (N=3, p<0.01). Furthermore, mice with fibroblast-specific CCN1 knockout (Pdgfra-CreER;CCN1fl/fl) displayed reduced tumor development following two-stage chemical carcinogenesis (N=5, p<0.01) or chronic exposure to ultraviolet irradiation (UV) (N=6, p<0.01). These findings highlight the critical role of age-related changes in the dermal microenvironment that enable keratinocyte cancer development and advance understanding of the mechanisms involved in the heightened prevalence of skin cancer among older populations. Taihao Quan¹, Chunfang Guo¹, Junyoung Kim¹, Ava J. Kim¹, John J. Voorhees¹, Andrzej Dlugosz¹, Gary J. Fisher¹ 1. Department of Dermatology, University of Michigan, Ann Arbor, MI, United States. UV Biology/Injury and Non-melanoma Cancers