SENESCENT STROMA STIMULATES INFLAMMATION TO PROMOTE TUMORIGENESIS

摘要 年龄是癌症发展的一个重要风险因素。驱动这种风险的机制是复杂的 并且涉及细胞自主突变在初期肿瘤细胞内的积累和促肿瘤发生 肿瘤微环境的变化。研究老化微环境对 肿瘤发生已经揭示衰老的基质细胞可以直接刺激肿瘤前和肿瘤形成， 增长由于衰老细胞随着年龄的增长而积累，这些观察结果提高了衰老细胞 细胞是与年龄相关的肿瘤发生增加的重要因素。为了了解衰老是如何 基质细胞有助于肿瘤发生，我们开发了FASST小鼠（成纤维细胞加速基质细胞， 支持肿瘤发生），使我们能够控制衰老的空间和时间激活， 间充质细胞使用这种小鼠，我们发现衰老小鼠皮肤成纤维细胞（MSFs）支持增加， 免疫活性小鼠中的肿瘤发生。引人注目的是，我们发现，MSF的产生独立于肿瘤， 细胞通过调节宿主免疫系统并产生 免疫抑制限制了CD 8 T细胞的活性，从而增加了肿瘤的生长。先前的工作已经 集中于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 显示衰老的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引起免疫抑制细胞的局部募集，类似于我们在 老化的人类皮肤，我们提出，他们有助于与年龄相关的增加，在肿瘤的形成，通过创造区域 局部免疫抑制的作用，保护了初期的肿瘤细胞并使其生长。了解 在FASST模型中的免疫调节动力学，我们建议确定免疫调节的时间模式， 细胞浸润，驱动免疫细胞浸润的机制，以及驱动免疫细胞浸润的衰老特异性因素。 FASST小鼠中存在的抑制性微环境的发展和维持。进一步 我们建议检查衰老的基质细胞对鳞状细胞自发模型的影响， 癌（SCC，K14-HPV 16），其中100%的动物发生增生，但只有20%转化为SCC。这里 我们认为，基质区室中衰老的激活将增加这种细胞的凋亡率。 通过改变免疫环境来建立模型。最后，我们将探讨p38 MAPK依赖性衰老是如何与 分泌表型（SASP）因子有助于衰老细胞产生的免疫抑制环境。 基质细胞，并在临床前环境中询问靶向p38 MAPK或其下游激酶MK2是否是有效的 减少衰老基质支持的肿瘤发生的方法。该提案中的数据将提供重要的 机制的洞察力和新的治疗目标，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.