Integrative Analysis of the Aging Peritoneum in Metastatic Receptivity

这项建议的总体目标是提供一个全面的研究、培训和职业发展计划，使首席研究员能够顺利完成她的博士学位，并获得一个竞争激烈的博士后职位，从事老龄化和癌症领域的翻译研究。第一阶段的重点是完成正在进行的博士培训，调查衰老微环境在卵巢癌(OvCa)转移中的作用。卵巢癌是最致命的妇科恶性肿瘤，也是美国女性癌症死亡的第五大原因，美国女性的5年生存率很低，因为75%的女性被诊断为腹膜内播散性(IP)转移。卵巢癌转移与大多数其他癌症的不同之处在于，细胞从原发肿瘤分离，进入腹膜腔，附着于腹膜间皮细胞(MC)单层，嵌入单层，并侵入间皮下基质，在那里增殖并形成继发性病变。衰老是卵巢癌发生发展的最大危险因素。一半的卵巢癌诊断病例是63岁以上的女性，年龄较大的卵巢癌患者死亡风险更高。尽管如此，年龄在卵泡发育领域的研究还不够深入。尽管腹膜与皮肤的表面积几乎相同，但年龄对腹膜的影响还没有得到系统的评估。使用三种不同的小鼠衰老和OvCa转移的临床前模型，我们的实验室先前证实了老年小鼠腹膜结构转移种植的增强，并伴有免疫细胞渗透的改变。目前在这一应用中的初步数据显示，在比较幼年和老年动物主要转移部位的腹膜胶原超微结构时，观察到明显的差异。此外，在一组体外实验中，使用年轻和老年小鼠的纯化胶原蛋白，我们发现与年轻小鼠相比，老年胶原蛋白对OvCa细胞的侵袭增加，尽管在粘附性或增殖性方面没有差异。也观察到对蛋白水解性重构的不同易感性。这一数据支持了我们的假设，即与年龄相关的转移环境的变化增强了老年患者卵巢癌的转移。这项拟议研究的第一阶段目标是识别能够靶向这些与年龄相关的胶原结构修饰的小分子，以减少老年小鼠的转移扩散。其他研究将评估腹膜腔的另一个主要组成部分，内脏脂肪细胞，并描述脂肪细胞蛋白质组与年龄相关的变化。第二阶段的目标将集中在老龄化癌症的免疫格局上。研究将集中在T细胞的渗透和免疫衰老随着年龄的增长。在整个培训中，强调衰老的多学科方面，将博士后对肿瘤转移微环境的关注与博士后对肿瘤免疫系统的关注相结合，将为研究衰老在免疫治疗中的作用和改善老年癌症患者免疫治疗反应的机制的翻译职业奠定基础。

The overall goal of this proposal is to provide a comprehensive plan of research training and career development to enable the principal investigator to successfully complete her PhD and acquire a competitive postdoctoral position performing translational research in the fields of aging and cancer. Phase I focuses on completion of ongoing PhD training investigating the role of the aging microenvironment in ovarian cancer (OvCa) metastasis. OvCa is the most fatal gynecologic malignancy and the 5th leading cause of overall cancer death among American women with a low 5-year survival rate, as 75% of women are diagnosed with disseminated intra-peritoneal (IP) metastasis. OvCa metastasis differs from most other cancers in that cells detach from the primary tumor, shed into the peritoneal cavity, adhere to the peritoneal mesothelial cell (MC) monolayer, intercalate within this layer, and invade into the submesothelial matrix, where they proliferate and form secondary lesions. Aging is the biggest risk factor for the development of OvCa. Half of OvCa diagnoses are in women over the age of 63, and older OvCa patients have a higher risk of mortality. Despite this, age is understudied in the OvCa field. Even though the peritoneum has near the same surface area as the skin, the effect of age on the peritoneum has not been systematically evaluated. Using three distinct murine pre-clinical models of aging and OvCa metastasis, our lab previously demonstrated enhanced metastatic seeding of peritoneal structures in aged mice accompanied by altered immune cell infiltration. Current preliminary data in this application show that there are distinct differences observed when comparing peritoneal collagen ultrastructure in young and aged animals at major metastatic sites. Moreover, using purified collagen from young versus aged mice in a panel of in vitro assays, we showed increased invasion of OvCa cells through aged collagen relative to young, despite no difference in adhesion or proliferation. Differential susceptibility to proteolytic remodeling was also observed. This data supports our hypothesis that age-related changes to the metastatic environment enhance ovarian cancer metastasis in aged patients. The Phase I goal of the proposed research is to identify small molecules that can target these age-related structural modifications in collagen with the goal of reducing metastatic dissemination in aged mice. Additional studies will evaluate the other major component of the peritoneal cavity, the visceral adipocytes, with characterization of age-related changes in the adipocytes proteome. The Phase II goal will focus on the immune landscape of an aging cancer. Studies will focus on T cell infiltration and immunosenescence with aging. The emphasis on multi-disciplinary aspects of aging throughout the training, combining a predoctoral focus on the tumor metastatic microenvironment and a postdoctoral focus on the tumor immune system will position the candidate for a translational career investigating the role of aging on immunotherapy and mechanisms by which to improve immunotherapy responses in aged cancer patients.