SENESCENT STROMA STIMULATES INFLAMMATION TO PROMOTE TUMORIGENESIS

摘要 年龄是罹患癌症的重要危险因素。驱动这种风险的机制是复杂的。 它既涉及早期肿瘤细胞内细胞自主突变的积累，也涉及促肿瘤形成 肿瘤微环境的变化。老龄化微环境对人体健康影响的调查 肿瘤发生学研究表明，衰老的基质细胞可以直接刺激癌前病变和肿瘤 成长。因为衰老的细胞随着年龄的增长而积累，这些观察结果增加了衰老的可能性 细胞是与年龄相关的肿瘤形成增加的重要因素。去了解衰老的原因 基质细胞有助于肿瘤的发生，我们培育了FASST小鼠(成纤维细胞加速基质- 支持肿瘤发生)，使我们能够控制衰老的空间和时间激活 间充质细胞。利用这只小鼠，我们发现衰老的小鼠皮肤成纤维细胞(MSF)的支持度增加 免疫能力强的小鼠的肿瘤发生。令人惊讶的是，我们发现与肿瘤无关的MSF 细胞通过调节宿主免疫系统和产生 免疫抑制，限制CD8 T细胞活性，从而促进肿瘤生长。以前的工作有 重点研究衰老成纤维细胞直接刺激肿瘤细胞生长的能力。因此，我们的工作是第一个 表明衰老的MSF可以通过调节免疫系统促进肿瘤生长。因为我们发现 在我们的模型中，衰老的MSF导致免疫抑制细胞的局部招募，类似于我们在 老化的人类皮肤，我们认为它们通过创建区域来促进与年龄相关的肿瘤发生的增加 局部免疫抑制，保护初生的肿瘤细胞并使其生长。要了解 免疫调节的动力学在FASST模型中，我们建议确定免疫的时间模式 细胞渗透，驱动免疫细胞渗透的机制，以及驱动衰老的特定因素 FASST小鼠体内抑制微环境的发展和维持。进一步 我们建议研究衰老的间质细胞对自发性鳞状细胞模型的影响。 鳞癌(SCC，K14-HPV16)，100%的动物发生增生，但只有20%的动物转化为SCC。这里 我们认为，基质室内衰老的激活将增加这一区域的外显率。 通过改变免疫环境来建立模型。最后，我们将询问p38MAPK依赖的衰老是如何与 分泌表型(SASP)因子参与衰老所形成的免疫抑制环境 在临床前环境中询问靶向p38MAPK或其下游的MK2是否是有效的 减少衰老的间质支持的肿瘤发生的方法。来自该提案的数据将提供至关重要的 机制洞察力和新的治疗靶点，可能会减少与年龄相关的癌症增加。

Abstract Age is a significant risk factor for the development of cancer. The mechanisms that drive this risk are complex and involve both the accumulation of cell autonomous mutations within incipient tumor cells and pro-tumorigenic changes in the tumor microenvironment. Investigation into the impact of an aging microenvironment on tumorigenesis has revealed that senescent stromal cells can directly stimulate preneoplastic and neoplastic growth. Because senescent cells accumulate with age, these observations raise the possibility that senescent cells are an important contributor to age-related increases in tumorigenesis. To understand how senescent stromal cells contribute to tumorigenesis, we developed the FASST mouse (Fibroblasts Accelerate Stromal- Supported Tumorigenesis) that allows us to control the spatial and temporal activation of senescence in mesenchymal cells. Using this mouse, we found that senescent mouse skin fibroblasts (MSFs) support increased tumorigenesis in immunocompetent mice. Strikingly, we found that MSFs that arise independently of neoplastic cells mediate their pro-tumorigenic properties by modulating the host immune system and creating immunosuppression that limits CD8 T cell activity, thus allowing increased tumor growth. Previous work has focused on the ability of senescent fibroblasts to directly stimulate tumor cell growth. Thus our work is the first to show that senescent MSFs can promote tumor growth by modulating the immune system. Because we find that senescent MSFs in our model cause localized recruitment of immunosuppressive cells, similar to what we find in aging human skin, we propose that they contribute to age-related increases in tumorigenesis by creating regions of local immune suppression that shelter incipient tumor cells and allow their outgrowth. To understand the dynamics of immune modulation in the FASST model, we propose to determine the temporal pattern of immune cell infiltration, the mechanisms that drive immune cell infiltration, and the senescence-specific factors that drive the development and maintenance of the suppressive microenvironment present in the FASST mouse. Further we propose to examine the impact of senescent stromal cells on a spontaneous model of squamous cell carcinoma (SCC, K14-HPV16) where 100% of animals develop hyperplasia yet only 20% convert to SCC. Here we propose that the activation of senescence within the stromal compartment will increase the penetrance in this model by altering the immune landscape. Finally, we will ask how p38MAPK-dependent senescence-associated secretory phenotype (SASP) factors contribute to the immunosuppressive environment created by senescent stromal cells and ask in a preclinical setting if targeting p38MAPK or its downstream kinase MK2 is a valid approach to reducing senescent stromal-supported tumorigenesis. Data from this proposal will provide vital mechanistic insight and novel therapeutic targets that may reduce age-related increases in cancer.