The impact of the dermal ECM microenvironment on cutaneous aging and cancer

ABSTRACT The major goal of this grant application is to determine the molecular mechanisms by which age-related elevation of matrix metalloproteinase-1 (MMP1) in dermal fibroblasts creates a microenvironment that promotes the aging process and age-related skin pathologies, including cancer. Aging affects all individuals and is the single greatest risk factor for most common diseases, including cancer. The characteristic features of aged human skin include dermal thinning, wrinkles, sagging and loss of elasticity, resulting from disruption and degradation of collagen, the major structural protein in skin. Deterioration of dermal collagen fibrils is also directly connected to age‐related skin morbidities, such as tearing, bruising, poor wound healing, and critically contributes to weakened immunity, and cancer. We found that matrix metalloproteinase-1 (MMP1), which initiates cleavage of collagen fibrils, is significantly increased in aged human skin dermal fibroblasts. This increase is associated with fragmentation and disorganization of collagen fibrils and creates age-related aberrant extracellular matrix (ECM) microenvironment in the dermis (dermal aging). Based on above human skin in vivo data, we have recently generated a mouse model of skin dermal aging by fibroblast-specific expression of human MMP1, the source of the elevated MMP-1 in aged human skin, driven by a stromal cell-specific pdgfra-Cre transgene (pdgfra-Cre;MMP1). pdgfra-Cre;MMP1 mice exhibit significantly accelerated dermal aging, which closely mimics those observed in aged human skin. Importantly, pdgfra-Cre;MMP1 mice have substantially increased susceptibility to skin cancer/papilloma development, suggesting dermal aging microenvironment promotes age-related keratinocyte skin cancer. Based on these findings, we hypothesize that age-related elevation of MMP1 in dermal fibroblasts leads to progressive alterations of the dermal ECM, which creates a microenvironment that promotes the dermal aging process and age-related skin pathologies, including cancer. This data-driven hypothesis is based on a novel concept that skin dermal aging is governed by the adaptation of fibroblasts to the surrounding extracellular matrix (ECM) microenvironment (outside-in adaptation), rather than cell‐autonomous factors. We propose following Specific Aims to test above hypothesis. Aim 1: Determine the Molecular Signatures/Pathways During Dermal Aging Process. Aim 2: Investigate Mechanisms by which Dermal Aging is Driven by Fibroblast Adaptation to the Surrounding ECM Microenvironment in a Non-Cell-Intrinsic Manner. Aim 3: Define the Impact of Ageing of the Dermal Microenvironment on Keratinocyte Cancer Initiation. This proposal is innovative and may have profound impact on the field of aging and age-related diseases by identifying age- related ECM microenvironment as a key target for therapeutic intervention.