Regulation of Oncogene-Induced Senescence by Wnt-Signaling

描述(由申请人提供)：癌症的发展通常是一个多步骤的过程，依赖于肿瘤细胞中的许多遗传和表观遗传变化。此外，肿瘤细胞和细胞外生长信号之间的相互作用调节了癌症的进展。这项应用研究了基因改变和特定的细胞外生长信号如何相互作用来调节肿瘤的进展。获得单一激活癌基因的哺乳动物细胞经常进入不可逆转的增殖停滞状态，称为衰老。这种“癌基因诱导的衰老”起到了重要的肿瘤抑制作用，阻止了新生肿瘤细胞的增殖，从而阻止了它们沿着肿瘤发生的途径发展。这种机制抑制了几种癌症的形成，包括人类黑色素瘤、人类前列腺癌、小鼠的T细胞淋巴瘤，可能还有结肠癌。最引人注目的是，良性人类痣(Moles)是由黑素细胞组成的肿瘤前病变，通过RAS信号通路的致癌激活而衰老。在哺乳动物组织中，典型的Wnt信号通路通常维持细胞的增殖，例如成年组织干细胞。这一途径由细胞外Wnt配体激活，触发一系列细胞质和核事件，最终导致增殖基因的表达。最近，我们发现Wnt信号可以拮抗癌基因诱导的衰老，反之亦然。这表明这两个非常重要的细胞增殖控制过程之间存在着以前未被认识到的相互作用，这两个过程都对癌症具有重要意义。特别是，这些结果表明，细胞外生长信号，如典型的Wnt配体，可以通过影响癌基因诱导的衰老的效率和由此产生的肿瘤抑制活性来调节癌症的进展。我们将通过以下具体目标来检验这些想法：具体目标1.确定Wnt信号如何抑制癌基因诱导的衰老。具体目的2.研究Wnt信号是否通过抑制癌基因诱导的黑素细胞衰老来驱动黑色素瘤的形成。具体目的3.研究Wnt信号是否通过抑制癌基因诱导的结肠上皮细胞衰老而导致结肠癌。公共卫生相关性：最近，我们发现Wnt信号(促进肿瘤)抑制癌基因诱导的衰老(抑制肿瘤)。我们将测试这种新发现的功能相互作用是否有助于体内肿瘤的进展。具体来说，我们将重点关注黑色素瘤和结肠癌，这两种癌症在美国每年导致约6万人死亡。

DESCRIPTION (provided by applicant): Development of cancer is typically a multi-step process that depends on many genetic and epigenetic alterations in the tumor cells. In addition, cancer progression is modulated by interactions between the tumor cells and extracellular growth signals. This application investigates how genetic alterations and specific extracellular growth signals interact to modulate tumor progression. Mammalian cells that acquire a single activated oncogene frequently enter a state of irreversible proliferation arrest, called senescence. This "oncogene-induced senescence" acts an important tumor suppression process, by arresting proliferation of nascent tumor cells and therefore preventing their progression along a tumorigenic pathway. Formation of several cancers is suppressed by this mechanism, including human melanomas, human prostate cancer, T-cell lymphomas in mice and, likely, colon cancers. Most strikingly, benign human nevi (moles) are pre-neoplastic lesions comprised of melanocytes, made senescent by oncogenic activation of the Ras-signaling pathway. In mammalian tissues, the canonical Wnt-signaling pathway typically maintains cell proliferation, for example of adult tissue stem cells. This pathway is activated by extracellular Wnt ligands that trigger a cascade of cytoplasmic and nuclear events, culminating in expression of proliferative genes. Recently, we found that Wnt-signaling antagonizes oncogene-induced senescence, and vice versa. This points to a previously unappreciated cross-talk between these two very important cell proliferation- control processes, both of great significance to cancer. In particular, these results suggest that extracellular growth signals, such as canonical Wnt ligands, can modulate cancer progression by affecting the efficiency of oncogene-induced senescence and its resultant tumor suppression activity. We will test these ideas through the following Specific Aims: Specific Aim 1. Define how Wnt-signaling suppresses oncogene-induced senescence. Specific Aim 2. Investigate whether Wnt-signaling drives melanoma formation by inhibiting oncogene- induced senescence in melanocytes. Specific Aim 3. Investigate whether Wnt-signaling drives colon cancer by inhibiting oncogene-induced senescence in colonic epithelial cells. PUBLIC HEALTH RELEVANCE: Recently, we found that Wnt signaling (tumor-promoting) suppresses oncogene-induced senescence (tumor-suppressing). We will test whether this new-found functional interaction contributes to tumor progression in vivo. Specifically, we will focus on melanoma and colon cancer, two cancers which between them kill about 60,000 people a year in the United States.