Role of Integrin-linked kinase in skin homeostasis and carcinogenesis

表皮（皮肤）肿瘤是欧洲最常见的癌症类型。表皮暴露于广泛的环境损伤，包括紫外线照射和化学致癌物。因此，表皮角质形成细胞具有获得致癌突变的高风险。然而，相对较少的皮肤癌发展，因为大多数获得突变的细胞要么通过正常的终末分化过程丢失，要么通过被称为衰老的细胞周期停滞的永久状态的激活而丢失。因此，分析可以与癌基因协同作用的因素对于理解癌症进展的机制至关重要。我们先前分析了小鼠缺乏整合素连接激酶（ILK），β 1整合素粘附受体的中央效应，在他们的皮肤。这些小鼠在表皮中的增殖和终末分化之间的平衡中显示出深刻的缺陷。因此，ILK调节表皮细胞的稳态和增殖分化开关是明确的，但这种调节的分子机制尚不清楚。该项目的目的是了解中央粘附信号适配器整合素连接激酶（ILK）如何调节皮肤中的SC稳态，特别是通过其对基质重塑的影响。我们进一步的目标是揭示如何在SC稳态和细胞命运的决定损害有助于皮肤癌的发生。这些研究的长期目标是精确地了解细胞-基质相互作用如何通过其调节生长因子生物利用度和活化的能力来调节人类癌症的发生和进展。

Epidermal (skin) tumors are the most common type of cancer in Europe. The epidermis is exposed to a wide range of environmental insults, including ultraviolet irradiation and chemical carcinogens. As a result, epidermal keratinocytes have a high risk of acquiring an oncogenic mutation. However, relatively few skin cancers develop because most cells that acquire mutations are either lost through the normal process of terminal differentiation or activation of a permanent state of cell cycle arrest termed senescence. Therefore, the analysis of factors that can co-operate with oncogenes is critical for understanding the mechanisms of cancer progression. We have previously analyzed mice lacking Integrin-linked kinase (ILK), a central effector of beta1 integrin adhesion receptor, in their skin. These mice display a profound defect in the balance between proliferation and terminal differentiation in the epidermis. Therefore it is clear that ILK regulates epidermal homeostasis and the proliferation-differentiation switch of the epidermal keratinocytes, but the molecular mechanisms of this regulation are still unclear. The aim of this project is to understand how the central adhesion signaling adaptor Integrin-linked kinase (ILK) regulates SC homeostasis in the skin, in particular through its effect on the matrix remodeling. We further aim to uncover how impairments in SC homeostasis and cell fate decisions contribute to skin carcinogenesis. The long-term goal of these studies is to precisely understand how cell-matrix interactions, through their ability to regulate growth factor bioavailability and activation, regulate cancer initiation and progression in humans.